Chem Biol Drug Des 2015; 85: 1–3 Commentary
Small Steps to New Drugs for Bugs Roberta J. Melander1,* and David L Selwood2 1
Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA 2 The Wolfson Institute for Biomedical Research, Gower Street, London, WC1E 6BT, UK *Corresponding author: Roberta Melander, [email protected] Governments, academics and industry are beginning to listen to the medical communities call for new antibacterials. This special issue brings together diverse review articles on topics from economics and pricing to new discovery methods.
Key words: antibacterial drug discovery, antibiotic resistance, novel antibacterial strategies
In this special issue, we focus on the field of antibacterial drug discovery, in response to the rising global problem of antibiotic resistance. The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria is a considerable global public health threat, seriously threatening the vast medical advancements made possible by antibiotics. Exacerbating this problem is a lack of investment in antibiotic discovery by the pharmaceutical industry, partly as a result of the perceived inherently low rate of return for antibiotics compared to drugs targeted at chronic diseases. In addition, the well-documented failure of high throughput approaches to antibacterial drug discovery contributed to a low number of new antibiotics being developed around the turn of the century (1). This situation is so dire that the World Health Organization has identified multidrug-resistant (MDR) bacteria as one of the top three threats to human health (Fact sheet N°194 Updated April 2014), while the Infectious Diseases Society of America has issued a call to action from the biomedical community to deal with the MDR bacterial threat (the 10 9 ‘20 initiative aims to foster development of 10 innovative antibiotics by 2020). Further complicating the problem is that simply developing new bactericidal drugs may only provide a temporary solution, as bacteria invariably develop resistance to any introduced therapy that relies solely upon a single bacteriostatic/bactericidal mechanism. For example, daptomycin was introduced into the clinic in 2003, and less than a year later, the emergence of resisª 2015 John Wiley & Sons A/S. doi: 10.1111/cbdd.12482
tance was observed. As a result, alternative approaches to controlling bacterial infections are sorely needed, and such approaches are addressed in this issue. New initiatives to encourage the development of antibacterials have been announced, and the best known of these is the Generating Antibiotics Initiative Now (GAIN) act. Signed into law by President Obama in 2012, this scheme is similar to existing orphan drug designations and grants privileges to a qualifying therapy (Qualified Infectious Disease Product designation, QIDP). These are: a) an additional 5 years exclusivity, b) a priority review for marketing applications and c) successful products are eligible for a fast track designation. A list of qualifying pathogens was finalized in June 2014 and these are shown below (FDA– 2012–N–1037).
Acinetobacter species Aspergillus species Burkholderia cepacia complex Campylobacter species Candida species Clostridium difficile Enterobacteriaceae Enterococcus species Mycobacterium tuberculosis complex
Neisseria gonorrhoeae Neisseria meningitidis Non-tuberculous mycobacteria species Pseudomonas species Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Vibrio cholerae
Three additional pathogens were added following consultation. Coccidiodes species, Cryptococcus species, and Helicobacter pylori. The timescales of new drug discovery mean that the effect of new initiatives will not be seen for some time but they seem to offer a secure framework from which industry can plan a drug development program. In Europe some new initiatives include the DRIVE-AB project (Driving reinvestment in research and development and responsible antibiotic use) which seeks to encourage responsible antibiotic use and identify new economic models for the discovery of antibiotics. In the UK the government commissioned another review with initial findings expected in 2015 and recommendations in 2016 (UK Department of Health and Prime Ministers’ Office press release. The €85 million ENABLE (European Gram-Negative Antibacterial Engine) Horizon 2020 program brings together over 30 European universities and companies (including GSK) and has a tar1
Small Steps to New Drugs for Bugs
get of one new oral antibacterial in phase I by 2019. But is the regulatory and patent framework in place in Europe to ensure that new medicines will be commercial and approvable in a reasonable time? It is still possible to make money selling antibiotics; however, Daptomycin (Cubicin) had annualized sales of over $1 billion dollars worldwide in Q3 2014 and this is for an injectable therapy. Nor is it all gloom and doom in terms of new drugs, in 2014, three new therapies have been registered by the FDA all for the treatment of skin infections. Dalvance (dalbavancin) is an intravenous drug for the treatment of adults with skin infections caused by Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains) and Streptococcus pyogenes (FDA news release May 23, 2014). Sivextro (tedizolid phosphate), this is the only oral new drug of the three, for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) caused by Staphylococcus aureus (including methicillinresistant strains (MRSA) and methicillin-susceptible strains), Streptococcus species, and Enterococcus faecalis (FDA news release June 20, 2014). It is the second in the oxazolidinone class of antibiotics. Orbactiv (oritavancin) is an intravenous drug for the treatment of adults with skin infections caused by Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), various Streptococcus species, and Enterococcus faecalis (FDA news release August 6, 2014). NH
O O H 2N
O
O
NH NH
OH
O
N H
HN
HN
O H N
N H
OH
O HN
O H N O
N H
NH2
O
OH
O
O
NH
O
HN
Cl
OH N
HN
OH O
Cl H N
OH O
OH
O Cl
N N N
F N O HO P O OH
2
HO H2N
O
O
O O
HO
N O
N
OH OH
O
HN
N H O
H N
HO
Cl
O
H N
N H
OH OH
OH
O O
O
O
O H2N
O O
N H
O
McPhillie et al. (3) review novel approaches to the identification of novel antibacterial targets using various in silico methods, encompassing cheminformatic approaches such as on docking, pharmacophore, and ligand- and structure-based target prediction methods. The identification of new, previously unexplored, protein targets will likely circumvent existing resistance mechanisms that exist for current antibacterial targets. Durrant and Amaro (4) also address the use of computeraided drug discovery techniques for the identification of new antibacterial therapeutics. They discuss two machinelearning techniques, neural networks, and decision trees, which have been used to identify potential antibiotics that were subsequently experimentally validated. Zambelloni et al. (5) review antivirulence drugs that interfere with various aspects of bacterial pathogenicity. Approaches discussed include type III secretion system (T3SS) inhibitors, quorum sensing inhibitors, lethal factor inhibitors, and pilicides. Inhibitors of virulence factors in Vibrio cholera, the causative agent of cholera, are described, including the potent cholera toxin inhibitor virstatin, which reduced V. cholera colonization in a mouse model by selectively targeting the transcriptional factor ToxT.
OH
O
HN
O
O
OH
HO OH O
O O
HO
OH
OH Cl NH
O
O NH
HO
NH OH
O O
O O
O OH
O O
O
NH O O
OH NH
O
H 2N O
HO
HN O
NH O
O
H N
The reviews and articles in this special issue cover a wide range of relevant topics from pricing to new therapies to the effective use of adjuvants. From an economic standpoint, the cost-effectiveness of developing new antibiotics is reviewed and drug pricing addressed by Verhoef and Morris (2). Several cost-effectiveness analyses of new antibacterial agents are examined, with most showing that new antibacterial drugs were costeffective compared to older generation drugs. The use of value-based pricing to determine a price for new antibacterial agents at which these drugs provide value for money is discussed.
H N
McShan and De Guzman (6) discuss the potential of the T3SS as a Gram-negative antibacterial target in detail. Several classes of small molecule T3SS inhibitors are described including salicylidene acylhydrazides, thiazolidinones, and benzimidazoles, while non-small molecule inhibitors discussed include the glycoprotein lactoferrin. Alternative approaches to the development of new therapeutics, which are not based on traditional microbicidal entities, may also play a role in combating the problem of increasing antibiotic resistance. Such approaches, in which the drugs are not directly killing bacteria, may have the advantage of lowering pressure on bacteria to evolve resistance. Gill et al. (7) review one approach, the development of adjuvant drugs that could be employed in combination with traditional antibiotics to prolong the life span of the current antibiotic armory. Discussed are antiresistance Chem Biol Drug Des 2015; 85: 1–3
Melander and Selwood
drugs, which aim to potentiate the effects of current antimicrobials such as ß-lactamase inhibitors, efflux pump inhibitors, outer membrane permeabilizers, and antibiofilm drugs; antivirulence drugs including quorum sensing inhibitors and type II/III secretion system inhibitors; and hostdirected therapies that support the host immune system to facilitate infection clearance such as immunomodulatory peptides. Li et al. (8) report the rational design and synthesis of a novel series of 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolone hybrid antibiotics with potent Gram-positive activity. The lead compound from this series, the moxifloxacin analog 6n, exhibits minimum inhibitory concentrations (MICs) of 0.125 lg/mL or lower against strains of methicillin-susceptible Staphylococcus aureus and S. epidermidis and an MIC of 2 lg/mL against methicillin-resistant S. aureus (MRSA). This compound also exhibited some Gram-negative activity with MICs of 1 lg/mL and 2 lg/mL against Klebsiella pneumoniae and Escherichia coli, respectively. Docking studies with topoisomerase II DNA gyrase revealed that the binding model of 6n was similar to that of gatifloxacin, with two additional hydrogen bonds formed by the introduced 2-hydroxy3-(nitroimidazolyl)-propyl group. Finally Liu et al. (9) investigate the antibacterial properties of a series of dihydroxy quaternary ammonium salts. The lead compound from this series displayed broad-spectrum antibacterial activity, inhibiting E. coli, S. aureus, and Bacillus subtilis.
of antibacterial discovery. Nat Rev Drug Discovery;6:29– 40. 2. Verhoef T.I., Morris S. (2015) Cost-effectiveness and pricing of antibacterial drugs. Chem Biol Drug Des;85:4–13. 3. McPhillie MJ, Cain RM, Narramore S, Fishwick CW, Simmons KJ (2015) Computational Methods to Identify New Antibacterial Targets. Chem Biol Drug Des; 85:22–29. 4. Durrant J.D., Amaro R.E. (2015) Machine-learning techniques applied to antibacterial drug discovery. Chem Biol Drug Des;85:14–21. 5. Riccardo Zambelloni R., Marquez R., Roe A.J. Development of anti-virulence compounds: a biochemical review. Chem Biol Drug Des;85:43–55. 6. McShan A.C., De Guzman R.N. (2015) The bacterial type III secretion system as a target for developing new antibiotics. Chem Biol Drug Des;85:30–42. 7. Gill E.E., Franco O.L., Hancock R.E.W. (2015) Antibiotic adjuvants: diverse strategies for controlling drug resistant pathogens. Chem Biol Drug Des;85:56–78. 8. Li Q.1, Xing J., Cheng H., Wang H., Wang J., Wang S., Zhou J., Zhang H. (2014) Design, Synthesis, Antibacterial Evaluation and Docking Study of Novel 2-Hydroxy3-(nitroimidazolyl)-propyl-derived Quinolone. Chem Biol Drug Des;85:79–90. 9. Liu W.S.1, Wang C.H., Sun J.F., Hou G.G., Wang Y.P., Qu R.J. (2014) Synthesis, Characterization and Antibacterial Properties of Dihydroxy Quaternary Ammonium Salts with Long Chain Alkyl Bromides. Chem Biol Drug Des;85:91–97.
References 1. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges
Chem Biol Drug Des 2015; 85: 1–3
3
Small Steps to New Drugs for Bugs Roberta J. Melander1,* and David L Selwood2 1
Department of Chemistry, North Carolina State University, Raleigh, NC, 27695, USA 2 The Wolfson Institute for Biomedical Research, Gower Street, London, WC1E 6BT, UK *Corresponding author: Roberta Melander, [email protected] Governments, academics and industry are beginning to listen to the medical communities call for new antibacterials. This special issue brings together diverse review articles on topics from economics and pricing to new discovery methods.
Key words: antibacterial drug discovery, antibiotic resistance, novel antibacterial strategies
In this special issue, we focus on the field of antibacterial drug discovery, in response to the rising global problem of antibiotic resistance. The emergence of resistance to multiple antimicrobial agents in pathogenic bacteria is a considerable global public health threat, seriously threatening the vast medical advancements made possible by antibiotics. Exacerbating this problem is a lack of investment in antibiotic discovery by the pharmaceutical industry, partly as a result of the perceived inherently low rate of return for antibiotics compared to drugs targeted at chronic diseases. In addition, the well-documented failure of high throughput approaches to antibacterial drug discovery contributed to a low number of new antibiotics being developed around the turn of the century (1). This situation is so dire that the World Health Organization has identified multidrug-resistant (MDR) bacteria as one of the top three threats to human health (Fact sheet N°194 Updated April 2014), while the Infectious Diseases Society of America has issued a call to action from the biomedical community to deal with the MDR bacterial threat (the 10 9 ‘20 initiative aims to foster development of 10 innovative antibiotics by 2020). Further complicating the problem is that simply developing new bactericidal drugs may only provide a temporary solution, as bacteria invariably develop resistance to any introduced therapy that relies solely upon a single bacteriostatic/bactericidal mechanism. For example, daptomycin was introduced into the clinic in 2003, and less than a year later, the emergence of resisª 2015 John Wiley & Sons A/S. doi: 10.1111/cbdd.12482
tance was observed. As a result, alternative approaches to controlling bacterial infections are sorely needed, and such approaches are addressed in this issue. New initiatives to encourage the development of antibacterials have been announced, and the best known of these is the Generating Antibiotics Initiative Now (GAIN) act. Signed into law by President Obama in 2012, this scheme is similar to existing orphan drug designations and grants privileges to a qualifying therapy (Qualified Infectious Disease Product designation, QIDP). These are: a) an additional 5 years exclusivity, b) a priority review for marketing applications and c) successful products are eligible for a fast track designation. A list of qualifying pathogens was finalized in June 2014 and these are shown below (FDA– 2012–N–1037).
Acinetobacter species Aspergillus species Burkholderia cepacia complex Campylobacter species Candida species Clostridium difficile Enterobacteriaceae Enterococcus species Mycobacterium tuberculosis complex
Neisseria gonorrhoeae Neisseria meningitidis Non-tuberculous mycobacteria species Pseudomonas species Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Vibrio cholerae
Three additional pathogens were added following consultation. Coccidiodes species, Cryptococcus species, and Helicobacter pylori. The timescales of new drug discovery mean that the effect of new initiatives will not be seen for some time but they seem to offer a secure framework from which industry can plan a drug development program. In Europe some new initiatives include the DRIVE-AB project (Driving reinvestment in research and development and responsible antibiotic use) which seeks to encourage responsible antibiotic use and identify new economic models for the discovery of antibiotics. In the UK the government commissioned another review with initial findings expected in 2015 and recommendations in 2016 (UK Department of Health and Prime Ministers’ Office press release. The €85 million ENABLE (European Gram-Negative Antibacterial Engine) Horizon 2020 program brings together over 30 European universities and companies (including GSK) and has a tar1
Small Steps to New Drugs for Bugs
get of one new oral antibacterial in phase I by 2019. But is the regulatory and patent framework in place in Europe to ensure that new medicines will be commercial and approvable in a reasonable time? It is still possible to make money selling antibiotics; however, Daptomycin (Cubicin) had annualized sales of over $1 billion dollars worldwide in Q3 2014 and this is for an injectable therapy. Nor is it all gloom and doom in terms of new drugs, in 2014, three new therapies have been registered by the FDA all for the treatment of skin infections. Dalvance (dalbavancin) is an intravenous drug for the treatment of adults with skin infections caused by Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains) and Streptococcus pyogenes (FDA news release May 23, 2014). Sivextro (tedizolid phosphate), this is the only oral new drug of the three, for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSI) caused by Staphylococcus aureus (including methicillinresistant strains (MRSA) and methicillin-susceptible strains), Streptococcus species, and Enterococcus faecalis (FDA news release June 20, 2014). It is the second in the oxazolidinone class of antibiotics. Orbactiv (oritavancin) is an intravenous drug for the treatment of adults with skin infections caused by Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), various Streptococcus species, and Enterococcus faecalis (FDA news release August 6, 2014). NH
O O H 2N
O
O
NH NH
OH
O
N H
HN
HN
O H N
N H
OH
O HN
O H N O
N H
NH2
O
OH
O
O
NH
O
HN
Cl
OH N
HN
OH O
Cl H N
OH O
OH
O Cl
N N N
F N O HO P O OH
2
HO H2N
O
O
O O
HO
N O
N
OH OH
O
HN
N H O
H N
HO
Cl
O
H N
N H
OH OH
OH
O O
O
O
O H2N
O O
N H
O
McPhillie et al. (3) review novel approaches to the identification of novel antibacterial targets using various in silico methods, encompassing cheminformatic approaches such as on docking, pharmacophore, and ligand- and structure-based target prediction methods. The identification of new, previously unexplored, protein targets will likely circumvent existing resistance mechanisms that exist for current antibacterial targets. Durrant and Amaro (4) also address the use of computeraided drug discovery techniques for the identification of new antibacterial therapeutics. They discuss two machinelearning techniques, neural networks, and decision trees, which have been used to identify potential antibiotics that were subsequently experimentally validated. Zambelloni et al. (5) review antivirulence drugs that interfere with various aspects of bacterial pathogenicity. Approaches discussed include type III secretion system (T3SS) inhibitors, quorum sensing inhibitors, lethal factor inhibitors, and pilicides. Inhibitors of virulence factors in Vibrio cholera, the causative agent of cholera, are described, including the potent cholera toxin inhibitor virstatin, which reduced V. cholera colonization in a mouse model by selectively targeting the transcriptional factor ToxT.
OH
O
HN
O
O
OH
HO OH O
O O
HO
OH
OH Cl NH
O
O NH
HO
NH OH
O O
O O
O OH
O O
O
NH O O
OH NH
O
H 2N O
HO
HN O
NH O
O
H N
The reviews and articles in this special issue cover a wide range of relevant topics from pricing to new therapies to the effective use of adjuvants. From an economic standpoint, the cost-effectiveness of developing new antibiotics is reviewed and drug pricing addressed by Verhoef and Morris (2). Several cost-effectiveness analyses of new antibacterial agents are examined, with most showing that new antibacterial drugs were costeffective compared to older generation drugs. The use of value-based pricing to determine a price for new antibacterial agents at which these drugs provide value for money is discussed.
H N
McShan and De Guzman (6) discuss the potential of the T3SS as a Gram-negative antibacterial target in detail. Several classes of small molecule T3SS inhibitors are described including salicylidene acylhydrazides, thiazolidinones, and benzimidazoles, while non-small molecule inhibitors discussed include the glycoprotein lactoferrin. Alternative approaches to the development of new therapeutics, which are not based on traditional microbicidal entities, may also play a role in combating the problem of increasing antibiotic resistance. Such approaches, in which the drugs are not directly killing bacteria, may have the advantage of lowering pressure on bacteria to evolve resistance. Gill et al. (7) review one approach, the development of adjuvant drugs that could be employed in combination with traditional antibiotics to prolong the life span of the current antibiotic armory. Discussed are antiresistance Chem Biol Drug Des 2015; 85: 1–3
Melander and Selwood
drugs, which aim to potentiate the effects of current antimicrobials such as ß-lactamase inhibitors, efflux pump inhibitors, outer membrane permeabilizers, and antibiofilm drugs; antivirulence drugs including quorum sensing inhibitors and type II/III secretion system inhibitors; and hostdirected therapies that support the host immune system to facilitate infection clearance such as immunomodulatory peptides. Li et al. (8) report the rational design and synthesis of a novel series of 2-hydroxy-3-(nitroimidazolyl)-propyl-derived quinolone hybrid antibiotics with potent Gram-positive activity. The lead compound from this series, the moxifloxacin analog 6n, exhibits minimum inhibitory concentrations (MICs) of 0.125 lg/mL or lower against strains of methicillin-susceptible Staphylococcus aureus and S. epidermidis and an MIC of 2 lg/mL against methicillin-resistant S. aureus (MRSA). This compound also exhibited some Gram-negative activity with MICs of 1 lg/mL and 2 lg/mL against Klebsiella pneumoniae and Escherichia coli, respectively. Docking studies with topoisomerase II DNA gyrase revealed that the binding model of 6n was similar to that of gatifloxacin, with two additional hydrogen bonds formed by the introduced 2-hydroxy3-(nitroimidazolyl)-propyl group. Finally Liu et al. (9) investigate the antibacterial properties of a series of dihydroxy quaternary ammonium salts. The lead compound from this series displayed broad-spectrum antibacterial activity, inhibiting E. coli, S. aureus, and Bacillus subtilis.
of antibacterial discovery. Nat Rev Drug Discovery;6:29– 40. 2. Verhoef T.I., Morris S. (2015) Cost-effectiveness and pricing of antibacterial drugs. Chem Biol Drug Des;85:4–13. 3. McPhillie MJ, Cain RM, Narramore S, Fishwick CW, Simmons KJ (2015) Computational Methods to Identify New Antibacterial Targets. Chem Biol Drug Des; 85:22–29. 4. Durrant J.D., Amaro R.E. (2015) Machine-learning techniques applied to antibacterial drug discovery. Chem Biol Drug Des;85:14–21. 5. Riccardo Zambelloni R., Marquez R., Roe A.J. Development of anti-virulence compounds: a biochemical review. Chem Biol Drug Des;85:43–55. 6. McShan A.C., De Guzman R.N. (2015) The bacterial type III secretion system as a target for developing new antibiotics. Chem Biol Drug Des;85:30–42. 7. Gill E.E., Franco O.L., Hancock R.E.W. (2015) Antibiotic adjuvants: diverse strategies for controlling drug resistant pathogens. Chem Biol Drug Des;85:56–78. 8. Li Q.1, Xing J., Cheng H., Wang H., Wang J., Wang S., Zhou J., Zhang H. (2014) Design, Synthesis, Antibacterial Evaluation and Docking Study of Novel 2-Hydroxy3-(nitroimidazolyl)-propyl-derived Quinolone. Chem Biol Drug Des;85:79–90. 9. Liu W.S.1, Wang C.H., Sun J.F., Hou G.G., Wang Y.P., Qu R.J. (2014) Synthesis, Characterization and Antibacterial Properties of Dihydroxy Quaternary Ammonium Salts with Long Chain Alkyl Bromides. Chem Biol Drug Des;85:91–97.
References 1. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL (2007) Drugs for bad bugs: confronting the challenges
Chem Biol Drug Des 2015; 85: 1–3
3
