Mitochondrion 16 (2014) 50–54
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Side effects of antibiotics during bacterial infection: Mitochondria, the main target in host cell Rochika Singh ⁎, Lakshmi Sripada, Rajesh Singh ⁎⁎ Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Gandhinagar, India
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Available online 16 November 2013 Keywords: Antibiotics Mitochondria Side effects Translational arrest
a b s t r a c t Antibiotics are frontline therapy against microbial infectious diseases. Many antibiotics are known to cause several side effects in humans. Ribosomal RNA (rRNA) is the main target of antibiotics that inhibit protein synthesis. According to the endosymbiont theory, mitochondrion is of bacterial origin and their molecular and structural components of the protein expression system are almost similar. It has been observed that the rate of mutations in mitochondrial rRNA is higher as compared to that of nuclear rRNA. The presence of these mutations may mimic prokaryotic rRNA structure and bind to antibiotics targeted to ribosomes of bacteria. Mitochondrial functions are compromised hence may be one of the major causes of side effects observed during antibiotic therapy. The current review had summarized the studies on the role of antibiotics on mitochondrial functions and its relevance to the observed side effects in physiological and pathological conditions. © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
1. Introduction Since the development of antibiotics, it had been the first line of treatment against many Gram positive and negative bacterial infections since the early twentieth century. The compounds that specifically target fundamental cellular processes of bacteria, with negative consequences for pathogen survival, and no plausible side effects in host are considered as potentially useful antibiotics (Dimauro and Davidzon, 2005; Fischel-Ghodsian, 2005; Wang et al., 2006). It has been observed that more than 40% of antibiotics interfere with bacterial protein biosynthesis machinery and more specifically the ribosome is one of the most important targets (McCoy et al., 2011). The two ribosomal subunits (30S and 50S) play an important role starting from initiation of elongation to termination of the translational process. The 30S subunit is responsible for codon–anticodon interactions. In the prokaryotic system, the translation is a complex process and involves several steps like initiation, elongation and termination which had been well established. The initiation of the translational is initiated by a complex of IF1, IF2 (a GTP-binding protein), IF3, mRNA and the initiator fMet-tRNAfMet which binds to the 30S ribosomal subunit, forming the 30S initiation complex (30S IC). In the next step, the 50S subunit joins the 30S IC and GTP is hydrolyzed. This leads to ⁎ Correspondence to: R. Singh, Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382007, India. Tel.: +91 79 30514245; fax: +91 79 30514110. ⁎⁎ Correspondence to: R. Singh, Department of Bio-Chemistry, Faculty of Science, Lokamanya Tilak Road, Sayajigunj, Vadodara, Gujarat 390005, India. Tel.: + 91 265 2795594. E-mail addresses: [email protected] (R. Singh), [email protected] (R. Singh).
the disassociation of the initiation factors and fMet-tRNAfMet is positioned in the P site. This complex is called as 70S initiation complex (70S IC). After binding of the first aminoacyl-tRNA and formation of the first peptide bond, the 70S IC enters the elongation cycle of translation and finally termination. The 50S subunit is responsible for the catalytic activity of the peptide bond formation. It had been observed that different steps of translational process are the direct target of different antibiotics. The mode of action at different steps of translation had been summarized in Table S1. The peptidyl transferase center (PTC) is the most conserved rRNA nucleotide in the entire ribosome. The recent findings revealed an unexpected high level of variation in the mode of antibiotic binding to the PTC of ribosomes from different organisms (Polacek and Mankin, 2005). The antibiotics chloramphenicol and oxazolidinones act on the PTC and cause myelosuppression, lactic acidosis and optic and peripheral neuropathies similar to phenotypes frequently found in mitochondriopathies (Bacino et al., 1995; Bitner-Glindzicz et al., 2010). Similarly, another group of antibiotics, erythromycin, tetracycline and aminoglycosides, which target large and small subunits of rRNA also showed similar side effects (Pasquale and Tan, 2005). These are also known to act on mitochondria and may cause bioenergetic crisis in a patient with Leber's hereditary optic neuropathy (LHON) disease (Thyagarajan et al., 2000). Mitochondria are now known to be involved in many other cellular processes other than energy metabolism like apoptosis and regulation of inflammation during viral and bacterial infections (Zhao et al., 2004). However, the action of antibiotics in the context of the newly discovered role of mitochondria has not been studied. The antibiotics had been extensively used as front-line therapy against many bacterial infections and are considered as life saving drugs. The side effects of
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R. Singh et al. / Mitochondrion 16 (2014) 50–54
antibiotics are emerging which have been summarized in Table S2. The majority of the antibiotics target the ribosome of bacteria to inhibit its translation, hence its growth. Due to the similarity of bacterial and mitochondrial ribosomes most of the antibiotics show side effects similar to mitochondrial myopathies. In the current review, we summarize the available literature in the area and emphasized the needs for further investigation to understand the side effects of antibiotics in human cells with special focus on mitochondria. 2. Antibiotic therapy in microbial infection and its side effects The emergence of antibiotic resistance in majority of pathogenic bacteria is a cause of major concern in infectious bacterial diseases therefore it is of urgent need to identify the antimicrobials which are more susceptible for microbial infections with minimal side effects on the host cell. The mechanism of acquisition of antibiotic resistance should be further investigated while developing new antibiotics taking their side effects into consideration. Protein synthesis is a key and universal process in all unicellular to multicellular organisms. The functional sites are highly evolutionary conserved within rRNAs. These sites are targeted by ribosomal drugs, which implies limitations with respect to selectivity and toxicity (Xing et al., 2006). The LHON patients when given erythromycin showed bilateral vision loss with optic nerve atrophy. The transmitochondrial cybrids derived from the patient showed bioenergetic crisis, impairment of cell growth in galactose medium and mitochondrial protein synthesis defects (Luca et al., 2004). Tetracycline is also known to cause several side effects by targeting cytochrome oxidase activity in thymocytes (Tanimoto et al., 2004) and HepG2 cells (Bottger et al., 2001). The aminoglycoside group of antibiotics is associated with both nephrotoxicity and ototoxicity (Polacek and Mankin, 2005). It has been shown that renal impairment is, in general, mild and reversible while ototoxicity is irreversible. The side effects of antibiotics are tissue specific (Borshchev et al., 2012; Marra et al., 2012; Neri et al., 2012; Roca-Alonso et al., 2012; Rouby et al., 2012; Scherzed et al., 2013; Siefker-Radtke et al., 2013). Several examples of the side effects have been summarized in Table S3 and many more examples can be found in the literature. The energy demand of individual organ systems is different (Peters et al., 2011) therefore the side effect of antibiotics related to mitochondria may vary. The nervous system is dependent on mitochondrial energy metabolism therefore it is severely affected by mitochondrial mutations. The pathologies associated with brain like optic neuropathy and sensorineural hearing loss are commonly observed (Table S3) during antibiotic therapy during bacterial infections (Polacek and Mankin, 2005). Remarkably, toxic optic neuropathy and ototoxicity are observed after the administration of different antibiotics, such as macrolides (Cotney et al., 2007) or chloramphenicol (Pacheu-Grau et al., 2010). Recently, 25 transmitochondrial cell lines derived from the platelets from individuals related with the most frequent available European mitochondrial DNA haplogroups. These cell lines were cultured in the presence/absence of antibiotics targeting for ribosomes (Pacheu-Grau et al., 2013). The treatment of linezolid showed low levels of mitochondrial translation products, MT-CO1/SDHA ratio and complex IV activity in the cybrids harboring common mutations. The linezolid also showed side effects obtund and disoriented in time and space (Kofoed and Vester, 2002). These evidences suggest that mitochondrial functions may be compromised during antibiotic therapy during bacterial/viral infections. The cell line study also suggests that mitochondrial mutation may further compound the side effects of antibiotics targeting bacterial ribosomes. 3. Mitochondria: Target of antibiotics Many of the antibiotics target bacterial protein synthesis machinery specifically ribosomal RNA (Table S1). According to the endosymbiotic
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theory as well as comparisons of rRNA sequences from bacteria and higher eukaryotes show high degree of similarity. Interestingly, inspite of these similarities there are differences in rRNA sequences, which are highly conserved which may have implication in drug sensitivity and selectivity (Harish and Caetano-Anolles, 2012). It had been observed that some of the resistance mutations in bacteria are present in human wild-type rRNA and can account for the antibiotic selectivity (Polacek and Mankin, 2005). The ribosomal peptidyl transferase center (PTC) plays a important role in protein synthesis and its function is inhibited by antibiotics like chloramphenicol and oxazolidinones (Carelli et al., 2002; Nagiec et al., 2005; Yunis, 1989). The treatment of the human tissues or cells with antibiotics, severely affects mitochondrial parameters and functions since the PTC mimics bacterial PTC (Fig. 1). The cell growth, mitochondrial mass, respiratory complex activities, levels of mtDNA-encoded subunits and mitochondrial protein synthesis are impaired with administration of antibiotics (Duewelhenke et al., 2007). Similarly, patient undergoing linezolid therapy for a long time showed defect in mitochondrial complexes. Similarly, a recent study systematically showed that antibiotics affected the mitochondrial functions in cell line studies and the side effects have been clearly observed in animal model studies as well. Kalghatgi showed that mice treated with clinically relevant doses of bactericidal antibiotics showed signs of oxidative damage on the transport chain, and increased levels of ROS. The antibiotics ciprofloxacin (a fluoroquinolone), ampicillin (a βlactam), and kanamycin (an aminoglycoside) in the mice showed decreased mitochondrial functions and increased levels of ROS (Kalghatgi et al., 2013). Interestingly, these parameters revert back to normal once the antibiotic is removed from the culture media (Pereira et al., 2009). The effect of antibiotics on mitochondrial function is also specific. Streptomycin affects mitochondrial translation in HeLa, cervical carcinoma cells having mtDNA 1555G N A mutation (McKee et al., 2006). This effect is specific as it does not happen on the 143B osteosarcoma cells with similar nuclear background and mtDNA mutation (Inoue et al., 1996). The mitochondrial genome encodes only for few functional proteins and many genes had been transferred to nuclear DNA during evolution. Nuclear DNA encodes most of the protein responsible (except 13 encoded from mitochondrial DNA) for mitochondrial function, hence, the nuclear genetic background will probably influence the toxicity produced by antibiotics. TFB1M is a nuclear encoded mitochondrial transcription factor and it is closely related to rRNA methyltransferases. The expression of TFB1M in Escherichia coli lacking the Ksg rRNA methyltransferase, helps in methylation of two adjacent adenine residues in a stem loop structure of the bacterial 16S rRNA leading to resistance to the antibiotic kasugamycin (Giordano et al., 2002). The polymorphism on chromosome 6 near the TFB1M gene, however not located in the coding region of the gene has been defined as a nuclear modifying locus and is responsible for mitochondrial functional defect leading to deafness (Guan et al., 2001). The 28 nucleotide residues downstream from the pathogenic 1555G N A mutation, are evolutionarily conserved in the mitochondrial 12S rRNA (Cotney et al., 2007). Interestingly, there is evidence that the nuclear genetic background influences the phenotypic expression of this mutation (Seidel-Rogol et al., 2003). Similarly, it had been observed that human cells (MCF12A) treated with doxycycline showed the alteration in nuclear gene expression that alters mitochondrial functions. It was observed that antibiotic treatment leads to a shift from TCA cycle to glycolytic pathway because of the upregulation expression of the gene involved in glycolytic pathway (Ahler et al., 2013). These evidences suggest that nuclear genes are obviously implicated in the modification or interaction with the mt-rRNAs. Hence, should be considered when analyzing the phenotypic effects of particular ribosomal antibiotics on the mitochondrial translation.
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Fig. 1. Mitochondria as a target of antibiotics. The antibiotics interfere with mitochondrial translational apparatus apart from targeting bacterial protein synthesis machinery. This leads to mitochondrial metabolic defects and cell death leading to the side effect of the antibiotics.
4. Mitochondrial genetic variation in contribution to antibiotic susceptibility Increasing evidences suggest that mtDNA is associated with different disorders affecting numerous organs and tissues (Dimauro and Davidzon, 2005). The mitochondrion is known as the power house providing adenosine triphosphate (ATP). The differential effects of mitochondrial DNA mutations are observed depending upon the bioenergetic requirement of the organ or tissue. The brain, heart, liver, muscle, endocrine, optical and auditory cells have high requirement of energy hence are more prone to side effects of antibiotics (Table S3). The human mitochondrial genome encodes 13 polypeptides for oxidative phosphorylation and 24 RNAs (2 rRNAs and 22 tRNAs) for translation in mitochondrial ribosomes (Taylor and Turnbull, 2005). Mitochondrial DNA is more prone to mutation as it is constantly exposed to oxidative environment in the cells. Therefore mitochondrial mutations and genetic variability may affect the antibiotic sensitivity to the host cell. For instance: aminoglycosides are one of the those which bind directly to the subunit of 16S and 30S of bacterial ribosomal RNA (rRNA) to initiate premature termination of the protein synthesis (Fischel-Ghodsian, 2005). The aminoglycoside ototoxicity revealed the identification of mitochondrial DNA mutation in 12S rRNA. The mitochondrial mutation A1555G, associated with ototoxicity was first described in a Chinese patient. Later, another mitochondrial mutation, C1494T mutation, was also identified in two Chinese families with hearing impairment with or without aminoglycoside treatment (Wang et al., 2006) and three Spanish individuals (Zhao et al., 2005). The mutations A1555G and C1494T are found in the highly preserved region of 12S rRNA, associated with the binding of the aminoglycoside to the bacteria (Zhao et al., 2005). The mutation in the conserved region of 12S rRNA leads to alteration in its secondary structure and increases the susceptibility of aminoglycosides and consequently its ototoxic effect (Postal et al., 2009; Prezant et al., 1993). The mitochondrial DNA mutation 1555A N G in children suffering with acute leukemia is sensitive to ototoxicity of aminoglycoside. The children diagnosed with
leukemia should be tested for this mutation and alternative antibiotics chosen for the treatment of bacterial infection. There are five mutations known in the mitochondrial gene encoding 12S rRNA (MT-RNR1) which cause hearing impairment if an aminoglycoside antibiotic is given during any bacterial infection (Akram et al., 2007) (Fig. 2). Similarly it had been observed that mitochondrial mutation leads to ototoxicity in a 79 year old patient who had a 45-year history of streptomycininduced tinnitus. The mitochondrial mutation 1556C N T was detected in the patient and was closely related to A1555 N G leading to sensitivity to the aminoglycoside group of antibiotics (Tanimoto et al., 2004). The role of 12S RNA is emerging and its relevance in antibiotic side effects needs to be further studied. The mitochondrial mutation, its sensitivity to antibiotics and observed side effects have been summarized (Table 1). The evidences cited here clearly suggest that the mitochondrial genetic variability may be one of the major causes of antibiotic sensitivity observed in the patients. Further study in this direction will emphasize to analyze the mitochondrial DNA sequence of the patients before the antibiotic therapy. This strategy may minimize the side effects observed in the patients. 5. Conclusion The acquisition of many rRNA mutations alters the antibiotic binding site which acquires the drug resistance. Certain resistance mutations in bacteria are present in human wild-type mt-rRNA resulting in affinity for antibiotic (Polacek and Mankin, 2005). The development of new antibiotics for the treatment of resistant microorganisms may be hindered because it is involved in increasing mitochondrial toxicity (Fig. 3). Moreover, many frequently used antibiotics impair mitochondrial physiology, hence it may be important to screen the patients for mitochondrial mutations before the prescription of the antibiotics. Nuclear DNA codes for most of the proteins required for the optimal function of the organelle. The nuclear background specifically related to mitochondria should be taken into consideration while selecting the antibiotics for therapy. Therefore it is important
R. Singh et al. / Mitochondrion 16 (2014) 50–54
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Fig. 3. Graphical summary of the possible role and side effects of antibiotics in human cell. The antibiotics turn out to be toxic to host organ systems by targeting mitochondrial protein synthesis machinery leading to metabolic dysregulation. Antibiotics can also target nontraditional role of mitochondrial metabolism, inflammation, cell death, and necrosis.
Fig. 2. Mutations in RNR1 enhances susceptibility to antibiotics. The human mitochondrial DNA (mtDNA) encodes 13 proteins and 24 ncRNAs. The 12S rRNA and 16S rRNA are conserved from prokaryotes to human mitochondria. The mutations in 12S rRNA (MT-RNR1) lead to translational defects in mitochondria.
to initiate studies in this direction. The long term strategy should include the understanding of patient's genetic background for optimum and efficacy of antibiotic therapy. This will not only help to prevent the occurrence of toxic side effects but will also increase the development of potential antibiotics. Mitochondria were traditionally regarded as the power house of the cell as it is associated with energy metabolism but recent work has shown that mitochondria have also a critical role to play in regulation of apoptosis and innate immunity. Mitochondrion senses the cellular stress and releases cytochrome C and other proteins which initiate a regulated proteolytic cascade by caspases leading
Table 1 Mitochondrial mutation and sensitivity to different antibiotics. Sr. no.
Antibioticsa
1
Aminoglycosides
2
Linezolid
3 4
Streptomycin Chloramphenicol
Mutations in mitochondrial genome
Side effects
m.C1494T m.A1555G m.A827G m.T1095C C.1645G A3243G EcA1408G m.A2706G m.G3010A m.G1555A m.C2939A/MT-RNR2 m.T2991C/MT-RNR2
Hearing loss, deafness
to cell death (Bykhovskaya et al., 2004). Similarly, death receptor pathways are also amplified by mitochondria through release of cytochrome C. The emerging evidences suggest that antibiotic can initiate energy crisis by compromising mitochondrial oxidative capacity. Therefore the role of antibiotics should be critically considered in this perspective. Recent experimental evidences suggest that mitochondria are not only important for apoptosis but also help to regulate innate immune response during viral and bacterial infections (Norberg et al., 2010). Mitochondrial antiviral signaling protein (MAVS) has been identified as an adaptor mitochondrial protein that may assemble signallosome linking upstream recognition of viral and bacterial infection to downstream activation of the innate immune pathways activating both NF-kB and IFN pathways (Subramanian et al., 2013). This results in regulation of pro-inflammatory cytokines and interferon production critical in regulation of innate immune response. Thus, mitochondrion is a critical regulator of apoptosis and innate immunity beside energy metabolism. However, the role of antibiotics on mitochondrial mediated apoptosis and inflammation has not been investigated. Similarly, it had been observed that type-I IFN is known to play a critical role in host immune response during bacterial infection. With mitochondria being now designated as the central sensor and regulator of innate immune response, it will be interesting to understand the role of antibiotics specifically targeting mitochondria on this arm of immune response. Many interesting aspects of antibiotics are still being overlooked. An investigation in this direction should be initiated to uncover the newer role of antibiotics during bacterial infections as well as in other pathological conditions. Acknowledgments
Lactic acidosis Ototoxicity, deafness Myelosuppression, lactic acidosis, ototoxicity, optic and peripheral neuropathies
The mutations in mitochondrial genome increase susceptibility to side effects. a Antibiotics that caused side effects.
The work on mitochondria in the lab (RS) is supported by the Department of Biotechnology, Govt. of India, the Department of Science and Technology, Govt. of India and the Indian Council of Medical Research (ICMR), Govt. of India. Dr. Rochika Singh had received the Young Scientist Fellow Program from the Department of Science and Technology, Govt. of India. Lakshmi Sripada received the Junior Research Fellowship from the University Grant Commission, Govt. of India. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.mito.2013.10.005.
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Mitochondrion journal homepage: www.elsevier.com/locate/mito
Side effects of antibiotics during bacterial infection: Mitochondria, the main target in host cell Rochika Singh ⁎, Lakshmi Sripada, Rajesh Singh ⁎⁎ Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Gandhinagar, India
a r t i c l e
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Available online 16 November 2013 Keywords: Antibiotics Mitochondria Side effects Translational arrest
a b s t r a c t Antibiotics are frontline therapy against microbial infectious diseases. Many antibiotics are known to cause several side effects in humans. Ribosomal RNA (rRNA) is the main target of antibiotics that inhibit protein synthesis. According to the endosymbiont theory, mitochondrion is of bacterial origin and their molecular and structural components of the protein expression system are almost similar. It has been observed that the rate of mutations in mitochondrial rRNA is higher as compared to that of nuclear rRNA. The presence of these mutations may mimic prokaryotic rRNA structure and bind to antibiotics targeted to ribosomes of bacteria. Mitochondrial functions are compromised hence may be one of the major causes of side effects observed during antibiotic therapy. The current review had summarized the studies on the role of antibiotics on mitochondrial functions and its relevance to the observed side effects in physiological and pathological conditions. © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
1. Introduction Since the development of antibiotics, it had been the first line of treatment against many Gram positive and negative bacterial infections since the early twentieth century. The compounds that specifically target fundamental cellular processes of bacteria, with negative consequences for pathogen survival, and no plausible side effects in host are considered as potentially useful antibiotics (Dimauro and Davidzon, 2005; Fischel-Ghodsian, 2005; Wang et al., 2006). It has been observed that more than 40% of antibiotics interfere with bacterial protein biosynthesis machinery and more specifically the ribosome is one of the most important targets (McCoy et al., 2011). The two ribosomal subunits (30S and 50S) play an important role starting from initiation of elongation to termination of the translational process. The 30S subunit is responsible for codon–anticodon interactions. In the prokaryotic system, the translation is a complex process and involves several steps like initiation, elongation and termination which had been well established. The initiation of the translational is initiated by a complex of IF1, IF2 (a GTP-binding protein), IF3, mRNA and the initiator fMet-tRNAfMet which binds to the 30S ribosomal subunit, forming the 30S initiation complex (30S IC). In the next step, the 50S subunit joins the 30S IC and GTP is hydrolyzed. This leads to ⁎ Correspondence to: R. Singh, Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat 382007, India. Tel.: +91 79 30514245; fax: +91 79 30514110. ⁎⁎ Correspondence to: R. Singh, Department of Bio-Chemistry, Faculty of Science, Lokamanya Tilak Road, Sayajigunj, Vadodara, Gujarat 390005, India. Tel.: + 91 265 2795594. E-mail addresses: [email protected] (R. Singh), [email protected] (R. Singh).
the disassociation of the initiation factors and fMet-tRNAfMet is positioned in the P site. This complex is called as 70S initiation complex (70S IC). After binding of the first aminoacyl-tRNA and formation of the first peptide bond, the 70S IC enters the elongation cycle of translation and finally termination. The 50S subunit is responsible for the catalytic activity of the peptide bond formation. It had been observed that different steps of translational process are the direct target of different antibiotics. The mode of action at different steps of translation had been summarized in Table S1. The peptidyl transferase center (PTC) is the most conserved rRNA nucleotide in the entire ribosome. The recent findings revealed an unexpected high level of variation in the mode of antibiotic binding to the PTC of ribosomes from different organisms (Polacek and Mankin, 2005). The antibiotics chloramphenicol and oxazolidinones act on the PTC and cause myelosuppression, lactic acidosis and optic and peripheral neuropathies similar to phenotypes frequently found in mitochondriopathies (Bacino et al., 1995; Bitner-Glindzicz et al., 2010). Similarly, another group of antibiotics, erythromycin, tetracycline and aminoglycosides, which target large and small subunits of rRNA also showed similar side effects (Pasquale and Tan, 2005). These are also known to act on mitochondria and may cause bioenergetic crisis in a patient with Leber's hereditary optic neuropathy (LHON) disease (Thyagarajan et al., 2000). Mitochondria are now known to be involved in many other cellular processes other than energy metabolism like apoptosis and regulation of inflammation during viral and bacterial infections (Zhao et al., 2004). However, the action of antibiotics in the context of the newly discovered role of mitochondria has not been studied. The antibiotics had been extensively used as front-line therapy against many bacterial infections and are considered as life saving drugs. The side effects of
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R. Singh et al. / Mitochondrion 16 (2014) 50–54
antibiotics are emerging which have been summarized in Table S2. The majority of the antibiotics target the ribosome of bacteria to inhibit its translation, hence its growth. Due to the similarity of bacterial and mitochondrial ribosomes most of the antibiotics show side effects similar to mitochondrial myopathies. In the current review, we summarize the available literature in the area and emphasized the needs for further investigation to understand the side effects of antibiotics in human cells with special focus on mitochondria. 2. Antibiotic therapy in microbial infection and its side effects The emergence of antibiotic resistance in majority of pathogenic bacteria is a cause of major concern in infectious bacterial diseases therefore it is of urgent need to identify the antimicrobials which are more susceptible for microbial infections with minimal side effects on the host cell. The mechanism of acquisition of antibiotic resistance should be further investigated while developing new antibiotics taking their side effects into consideration. Protein synthesis is a key and universal process in all unicellular to multicellular organisms. The functional sites are highly evolutionary conserved within rRNAs. These sites are targeted by ribosomal drugs, which implies limitations with respect to selectivity and toxicity (Xing et al., 2006). The LHON patients when given erythromycin showed bilateral vision loss with optic nerve atrophy. The transmitochondrial cybrids derived from the patient showed bioenergetic crisis, impairment of cell growth in galactose medium and mitochondrial protein synthesis defects (Luca et al., 2004). Tetracycline is also known to cause several side effects by targeting cytochrome oxidase activity in thymocytes (Tanimoto et al., 2004) and HepG2 cells (Bottger et al., 2001). The aminoglycoside group of antibiotics is associated with both nephrotoxicity and ototoxicity (Polacek and Mankin, 2005). It has been shown that renal impairment is, in general, mild and reversible while ototoxicity is irreversible. The side effects of antibiotics are tissue specific (Borshchev et al., 2012; Marra et al., 2012; Neri et al., 2012; Roca-Alonso et al., 2012; Rouby et al., 2012; Scherzed et al., 2013; Siefker-Radtke et al., 2013). Several examples of the side effects have been summarized in Table S3 and many more examples can be found in the literature. The energy demand of individual organ systems is different (Peters et al., 2011) therefore the side effect of antibiotics related to mitochondria may vary. The nervous system is dependent on mitochondrial energy metabolism therefore it is severely affected by mitochondrial mutations. The pathologies associated with brain like optic neuropathy and sensorineural hearing loss are commonly observed (Table S3) during antibiotic therapy during bacterial infections (Polacek and Mankin, 2005). Remarkably, toxic optic neuropathy and ototoxicity are observed after the administration of different antibiotics, such as macrolides (Cotney et al., 2007) or chloramphenicol (Pacheu-Grau et al., 2010). Recently, 25 transmitochondrial cell lines derived from the platelets from individuals related with the most frequent available European mitochondrial DNA haplogroups. These cell lines were cultured in the presence/absence of antibiotics targeting for ribosomes (Pacheu-Grau et al., 2013). The treatment of linezolid showed low levels of mitochondrial translation products, MT-CO1/SDHA ratio and complex IV activity in the cybrids harboring common mutations. The linezolid also showed side effects obtund and disoriented in time and space (Kofoed and Vester, 2002). These evidences suggest that mitochondrial functions may be compromised during antibiotic therapy during bacterial/viral infections. The cell line study also suggests that mitochondrial mutation may further compound the side effects of antibiotics targeting bacterial ribosomes. 3. Mitochondria: Target of antibiotics Many of the antibiotics target bacterial protein synthesis machinery specifically ribosomal RNA (Table S1). According to the endosymbiotic
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theory as well as comparisons of rRNA sequences from bacteria and higher eukaryotes show high degree of similarity. Interestingly, inspite of these similarities there are differences in rRNA sequences, which are highly conserved which may have implication in drug sensitivity and selectivity (Harish and Caetano-Anolles, 2012). It had been observed that some of the resistance mutations in bacteria are present in human wild-type rRNA and can account for the antibiotic selectivity (Polacek and Mankin, 2005). The ribosomal peptidyl transferase center (PTC) plays a important role in protein synthesis and its function is inhibited by antibiotics like chloramphenicol and oxazolidinones (Carelli et al., 2002; Nagiec et al., 2005; Yunis, 1989). The treatment of the human tissues or cells with antibiotics, severely affects mitochondrial parameters and functions since the PTC mimics bacterial PTC (Fig. 1). The cell growth, mitochondrial mass, respiratory complex activities, levels of mtDNA-encoded subunits and mitochondrial protein synthesis are impaired with administration of antibiotics (Duewelhenke et al., 2007). Similarly, patient undergoing linezolid therapy for a long time showed defect in mitochondrial complexes. Similarly, a recent study systematically showed that antibiotics affected the mitochondrial functions in cell line studies and the side effects have been clearly observed in animal model studies as well. Kalghatgi showed that mice treated with clinically relevant doses of bactericidal antibiotics showed signs of oxidative damage on the transport chain, and increased levels of ROS. The antibiotics ciprofloxacin (a fluoroquinolone), ampicillin (a βlactam), and kanamycin (an aminoglycoside) in the mice showed decreased mitochondrial functions and increased levels of ROS (Kalghatgi et al., 2013). Interestingly, these parameters revert back to normal once the antibiotic is removed from the culture media (Pereira et al., 2009). The effect of antibiotics on mitochondrial function is also specific. Streptomycin affects mitochondrial translation in HeLa, cervical carcinoma cells having mtDNA 1555G N A mutation (McKee et al., 2006). This effect is specific as it does not happen on the 143B osteosarcoma cells with similar nuclear background and mtDNA mutation (Inoue et al., 1996). The mitochondrial genome encodes only for few functional proteins and many genes had been transferred to nuclear DNA during evolution. Nuclear DNA encodes most of the protein responsible (except 13 encoded from mitochondrial DNA) for mitochondrial function, hence, the nuclear genetic background will probably influence the toxicity produced by antibiotics. TFB1M is a nuclear encoded mitochondrial transcription factor and it is closely related to rRNA methyltransferases. The expression of TFB1M in Escherichia coli lacking the Ksg rRNA methyltransferase, helps in methylation of two adjacent adenine residues in a stem loop structure of the bacterial 16S rRNA leading to resistance to the antibiotic kasugamycin (Giordano et al., 2002). The polymorphism on chromosome 6 near the TFB1M gene, however not located in the coding region of the gene has been defined as a nuclear modifying locus and is responsible for mitochondrial functional defect leading to deafness (Guan et al., 2001). The 28 nucleotide residues downstream from the pathogenic 1555G N A mutation, are evolutionarily conserved in the mitochondrial 12S rRNA (Cotney et al., 2007). Interestingly, there is evidence that the nuclear genetic background influences the phenotypic expression of this mutation (Seidel-Rogol et al., 2003). Similarly, it had been observed that human cells (MCF12A) treated with doxycycline showed the alteration in nuclear gene expression that alters mitochondrial functions. It was observed that antibiotic treatment leads to a shift from TCA cycle to glycolytic pathway because of the upregulation expression of the gene involved in glycolytic pathway (Ahler et al., 2013). These evidences suggest that nuclear genes are obviously implicated in the modification or interaction with the mt-rRNAs. Hence, should be considered when analyzing the phenotypic effects of particular ribosomal antibiotics on the mitochondrial translation.
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Fig. 1. Mitochondria as a target of antibiotics. The antibiotics interfere with mitochondrial translational apparatus apart from targeting bacterial protein synthesis machinery. This leads to mitochondrial metabolic defects and cell death leading to the side effect of the antibiotics.
4. Mitochondrial genetic variation in contribution to antibiotic susceptibility Increasing evidences suggest that mtDNA is associated with different disorders affecting numerous organs and tissues (Dimauro and Davidzon, 2005). The mitochondrion is known as the power house providing adenosine triphosphate (ATP). The differential effects of mitochondrial DNA mutations are observed depending upon the bioenergetic requirement of the organ or tissue. The brain, heart, liver, muscle, endocrine, optical and auditory cells have high requirement of energy hence are more prone to side effects of antibiotics (Table S3). The human mitochondrial genome encodes 13 polypeptides for oxidative phosphorylation and 24 RNAs (2 rRNAs and 22 tRNAs) for translation in mitochondrial ribosomes (Taylor and Turnbull, 2005). Mitochondrial DNA is more prone to mutation as it is constantly exposed to oxidative environment in the cells. Therefore mitochondrial mutations and genetic variability may affect the antibiotic sensitivity to the host cell. For instance: aminoglycosides are one of the those which bind directly to the subunit of 16S and 30S of bacterial ribosomal RNA (rRNA) to initiate premature termination of the protein synthesis (Fischel-Ghodsian, 2005). The aminoglycoside ototoxicity revealed the identification of mitochondrial DNA mutation in 12S rRNA. The mitochondrial mutation A1555G, associated with ototoxicity was first described in a Chinese patient. Later, another mitochondrial mutation, C1494T mutation, was also identified in two Chinese families with hearing impairment with or without aminoglycoside treatment (Wang et al., 2006) and three Spanish individuals (Zhao et al., 2005). The mutations A1555G and C1494T are found in the highly preserved region of 12S rRNA, associated with the binding of the aminoglycoside to the bacteria (Zhao et al., 2005). The mutation in the conserved region of 12S rRNA leads to alteration in its secondary structure and increases the susceptibility of aminoglycosides and consequently its ototoxic effect (Postal et al., 2009; Prezant et al., 1993). The mitochondrial DNA mutation 1555A N G in children suffering with acute leukemia is sensitive to ototoxicity of aminoglycoside. The children diagnosed with
leukemia should be tested for this mutation and alternative antibiotics chosen for the treatment of bacterial infection. There are five mutations known in the mitochondrial gene encoding 12S rRNA (MT-RNR1) which cause hearing impairment if an aminoglycoside antibiotic is given during any bacterial infection (Akram et al., 2007) (Fig. 2). Similarly it had been observed that mitochondrial mutation leads to ototoxicity in a 79 year old patient who had a 45-year history of streptomycininduced tinnitus. The mitochondrial mutation 1556C N T was detected in the patient and was closely related to A1555 N G leading to sensitivity to the aminoglycoside group of antibiotics (Tanimoto et al., 2004). The role of 12S RNA is emerging and its relevance in antibiotic side effects needs to be further studied. The mitochondrial mutation, its sensitivity to antibiotics and observed side effects have been summarized (Table 1). The evidences cited here clearly suggest that the mitochondrial genetic variability may be one of the major causes of antibiotic sensitivity observed in the patients. Further study in this direction will emphasize to analyze the mitochondrial DNA sequence of the patients before the antibiotic therapy. This strategy may minimize the side effects observed in the patients. 5. Conclusion The acquisition of many rRNA mutations alters the antibiotic binding site which acquires the drug resistance. Certain resistance mutations in bacteria are present in human wild-type mt-rRNA resulting in affinity for antibiotic (Polacek and Mankin, 2005). The development of new antibiotics for the treatment of resistant microorganisms may be hindered because it is involved in increasing mitochondrial toxicity (Fig. 3). Moreover, many frequently used antibiotics impair mitochondrial physiology, hence it may be important to screen the patients for mitochondrial mutations before the prescription of the antibiotics. Nuclear DNA codes for most of the proteins required for the optimal function of the organelle. The nuclear background specifically related to mitochondria should be taken into consideration while selecting the antibiotics for therapy. Therefore it is important
R. Singh et al. / Mitochondrion 16 (2014) 50–54
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Fig. 3. Graphical summary of the possible role and side effects of antibiotics in human cell. The antibiotics turn out to be toxic to host organ systems by targeting mitochondrial protein synthesis machinery leading to metabolic dysregulation. Antibiotics can also target nontraditional role of mitochondrial metabolism, inflammation, cell death, and necrosis.
Fig. 2. Mutations in RNR1 enhances susceptibility to antibiotics. The human mitochondrial DNA (mtDNA) encodes 13 proteins and 24 ncRNAs. The 12S rRNA and 16S rRNA are conserved from prokaryotes to human mitochondria. The mutations in 12S rRNA (MT-RNR1) lead to translational defects in mitochondria.
to initiate studies in this direction. The long term strategy should include the understanding of patient's genetic background for optimum and efficacy of antibiotic therapy. This will not only help to prevent the occurrence of toxic side effects but will also increase the development of potential antibiotics. Mitochondria were traditionally regarded as the power house of the cell as it is associated with energy metabolism but recent work has shown that mitochondria have also a critical role to play in regulation of apoptosis and innate immunity. Mitochondrion senses the cellular stress and releases cytochrome C and other proteins which initiate a regulated proteolytic cascade by caspases leading
Table 1 Mitochondrial mutation and sensitivity to different antibiotics. Sr. no.
Antibioticsa
1
Aminoglycosides
2
Linezolid
3 4
Streptomycin Chloramphenicol
Mutations in mitochondrial genome
Side effects
m.C1494T m.A1555G m.A827G m.T1095C C.1645G A3243G EcA1408G m.A2706G m.G3010A m.G1555A m.C2939A/MT-RNR2 m.T2991C/MT-RNR2
Hearing loss, deafness
to cell death (Bykhovskaya et al., 2004). Similarly, death receptor pathways are also amplified by mitochondria through release of cytochrome C. The emerging evidences suggest that antibiotic can initiate energy crisis by compromising mitochondrial oxidative capacity. Therefore the role of antibiotics should be critically considered in this perspective. Recent experimental evidences suggest that mitochondria are not only important for apoptosis but also help to regulate innate immune response during viral and bacterial infections (Norberg et al., 2010). Mitochondrial antiviral signaling protein (MAVS) has been identified as an adaptor mitochondrial protein that may assemble signallosome linking upstream recognition of viral and bacterial infection to downstream activation of the innate immune pathways activating both NF-kB and IFN pathways (Subramanian et al., 2013). This results in regulation of pro-inflammatory cytokines and interferon production critical in regulation of innate immune response. Thus, mitochondrion is a critical regulator of apoptosis and innate immunity beside energy metabolism. However, the role of antibiotics on mitochondrial mediated apoptosis and inflammation has not been investigated. Similarly, it had been observed that type-I IFN is known to play a critical role in host immune response during bacterial infection. With mitochondria being now designated as the central sensor and regulator of innate immune response, it will be interesting to understand the role of antibiotics specifically targeting mitochondria on this arm of immune response. Many interesting aspects of antibiotics are still being overlooked. An investigation in this direction should be initiated to uncover the newer role of antibiotics during bacterial infections as well as in other pathological conditions. Acknowledgments
Lactic acidosis Ototoxicity, deafness Myelosuppression, lactic acidosis, ototoxicity, optic and peripheral neuropathies
The mutations in mitochondrial genome increase susceptibility to side effects. a Antibiotics that caused side effects.
The work on mitochondria in the lab (RS) is supported by the Department of Biotechnology, Govt. of India, the Department of Science and Technology, Govt. of India and the Indian Council of Medical Research (ICMR), Govt. of India. Dr. Rochika Singh had received the Young Scientist Fellow Program from the Department of Science and Technology, Govt. of India. Lakshmi Sripada received the Junior Research Fellowship from the University Grant Commission, Govt. of India. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.mito.2013.10.005.
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