news & views ANTIFUNGAL DESIGN
The toxicity-resistance yin-yang
A modified amphotericin antifungal that is less toxic to human cells, owing to its increased preference for its fungal ergosterol target versus human cholesterol, can still evade the evolution of resistance.
David M Geiser
I
f you are being treated with the antifungal drug amphotericin B (AmB), you are in big trouble. For starters, you have a very serious fungal infection, perhaps the commensal yeast Candida in your blood, or worse, Aspergillus, a common environmental mold, growing in your body. You probably contracted this lifethreatening infection because you are severely immunocompromised, maybe because of HIV-AIDS or cytotoxic therapy in advance of a bone marrow or whole organ transplant. These conditions greatly reduce your body’s defense against these fungi, which otherwise are a harmless, normal component of your environment. Fortunately, AmB is quite effective across a broad range of fungi, and resistance is rare, so if the infection was caught in time, the drug will probably save your life. Unfortunately, it is also a very blunt instrument. It often causes severe side effects that include acute kidney toxicity, so it is generally reserved for infections that require aggressive treatment1,2. These side effects have earned it the nickname ‘ampho-terrible’ among clinicians. AmB is exemplary of a yin-yang model where drugs have a particularly effective mode of action and are less prone to evolution of resistance but, at the same time, are toxic. Davis et al.3 have now challenged this relationship by developing AmB analogs that retain effectiveness, with reduced host toxicities. Bacterial infections can be treated aggressively with antibiotics with few toxic side effects. Why is this not the case for fungi? Mostly, it is because the fungal and animal kingdoms are sisters in the tree of life, and there are few cellular functions that are unique to fungi and unshared with animals. AmB aims at the most commonly targeted trait that distinguishes fungi from animals: ergosterol, the lipid sterol equivalent of cholesterol found in animals. AmB acts as a sterol sponge, binding ergosterol and removing it from the cell membrane, disrupting multiple cellular functions4,5. Other antifungal drugs that target ergosterol, including triazoles and allylamines, do so by inhibiting its biosynthesis or normal accumulation in
the cell membrane. AmB’s mode of action via direct binding to its target may in part explain the lack of resistance evolution observed to the drugthere are severe fungal fitness tradeoffs between this resistance and virulence6. At the same time, AmB binds cholesterol as well as
ergosterol, most likely explaining its host toxicity7. Is it possible to decouple these factors and have an AmB that is less toxic but still retains its effectiveness? Hints of this possibility were identified in some allosteric properties of AmB. The authors OH
Me
OH
O
OH
C13
HO
Me
O
OH
OH
OH
OH
C16
O
O
Me O
O C3
C2
AmB
OH
OH Me HO
OH
OH
O Me
Me OH NH2
OH O
O
OH
OH
OH
OH
O
N H
N H
Me
Me O AmBMU
OH
OH Me HO
OH
O Me
Me OH NH2
O
OH O
O
OH
OH
OH
OH
O
N H
N H
NH2
Me O AmBAU
O OH
Me OH NH2
Figure 1 | The chemical structures of AmB and the urea derivatives. AmB methyl urea (AmBMU) and AmB amino urea (AmBAU) were developed by making them less able to act as a known ‘sterol sponge’ mechanism of AmB toward cholesterol (while still targeting ergosterol), and these still evade resistance. The modified C16 carboxyl position is depicted in blue, and the C3 methyl and the derivative ureas are in red.
nature chemical biology | Advance online publication | www.nature.com/naturechemicalbiology
1
news & views hypothesized that two polar interactions between the mycosamine appendage and the main carbon backbone of the molecule were responsible for its coaffinity with both cholesterol and ergosterol: a water bridge between the mycosamine C2 and C13 hydroxyl groups and a salt bridge between the mycosamine C3 amino group and the backbone C16 carboxyl. The work that proved this used a new ergosterol-specific AmB derivative dehydroxylated in the C2 of its mycosamine appendage, disrupting the water bridge7; however, synthesis of this form was not practical for large-scale production. The authors then focused on the C3 amino–C16 carboxyl interaction and developed a simple three-step synthesis that replaces the C16 carboxyl with various urea-derived forms. In vitro experiments using these AmB ureas demonstrated a lack of resistance evolution with much lower toxicity. This promising set of compounds (Fig. 1) should lead to new tools for the aggressive treatment of fungal infections,
2
without the terrible side effects that have given AmB its bad reputation. Even within the confines of a very limited set of functional targets, antifungal treatments have improved greatly in the last two decades. Liposomal preparations of AmB have permitted more targeted treatment, with reduced side effects. The use of triazoles, which are less toxic than AmB, has proven effective across a wide range of serious invasive infections, in many cases replacing its use. And new antifungal modes of action are being discovered, such as that mediated by oxaborole compounds, that may eventually be used to treat invasive infections. A less toxic version of AmB that is just as effective and not prone to the evolution of resistance would represent another major step forward in the improvement of the antifungal arsenal. Furthermore, the functional and biological approach used to identify these compounds can be applied to AmB for further refinement and for diverse
applications in fighting fungal infections in medicine and perhaps even in agriculture. ■ David M. Geiser is in the Department of Plant Pathology and Environmental Microbiology at Pennsylvania State University, University Park, Pennsylvania, USA. e-mail: [email protected] Published online 1 June 2015 doi:10.1038/nchembio.1838 References
1. Pappas, P.G. et al. Clin. Infect. Dis. 48, 503–535 (2009). 2. Walsh, T.J. et al. Clin. Infect. Dis. 46, 327–360 (2008). 3. Davis, S.A. et al. Nat. Chem. Biol. doi:10.1038/nchembio.1821 (1 June 2015). 4. Gray, K.C. et al. Proc. Natl. Acad. Sci. USA 109, 2234–2239 (2012). 5. Anderson, T.M. et al. Nat. Chem. Biol. 10, 400–406 (2014). 6. Vincent, B.M., Lancaster, A.K., Scherz-Shouval, R., Whitesell, L. & Lindquist, S. PLoS Biol. 11, e1001692 (2013). 7. Wilcock, B.C., Endo, M.M., Uno, B.E. & Burke, M.D. J. Am. Chem. Soc. 135, 8488–8491 (2013).
Competing financial interests The author declares no competing financial interests.
nature chemical biology | Advance online publication | www.nature.com/naturechemicalbiology
The toxicity-resistance yin-yang
A modified amphotericin antifungal that is less toxic to human cells, owing to its increased preference for its fungal ergosterol target versus human cholesterol, can still evade the evolution of resistance.
David M Geiser
I
f you are being treated with the antifungal drug amphotericin B (AmB), you are in big trouble. For starters, you have a very serious fungal infection, perhaps the commensal yeast Candida in your blood, or worse, Aspergillus, a common environmental mold, growing in your body. You probably contracted this lifethreatening infection because you are severely immunocompromised, maybe because of HIV-AIDS or cytotoxic therapy in advance of a bone marrow or whole organ transplant. These conditions greatly reduce your body’s defense against these fungi, which otherwise are a harmless, normal component of your environment. Fortunately, AmB is quite effective across a broad range of fungi, and resistance is rare, so if the infection was caught in time, the drug will probably save your life. Unfortunately, it is also a very blunt instrument. It often causes severe side effects that include acute kidney toxicity, so it is generally reserved for infections that require aggressive treatment1,2. These side effects have earned it the nickname ‘ampho-terrible’ among clinicians. AmB is exemplary of a yin-yang model where drugs have a particularly effective mode of action and are less prone to evolution of resistance but, at the same time, are toxic. Davis et al.3 have now challenged this relationship by developing AmB analogs that retain effectiveness, with reduced host toxicities. Bacterial infections can be treated aggressively with antibiotics with few toxic side effects. Why is this not the case for fungi? Mostly, it is because the fungal and animal kingdoms are sisters in the tree of life, and there are few cellular functions that are unique to fungi and unshared with animals. AmB aims at the most commonly targeted trait that distinguishes fungi from animals: ergosterol, the lipid sterol equivalent of cholesterol found in animals. AmB acts as a sterol sponge, binding ergosterol and removing it from the cell membrane, disrupting multiple cellular functions4,5. Other antifungal drugs that target ergosterol, including triazoles and allylamines, do so by inhibiting its biosynthesis or normal accumulation in
the cell membrane. AmB’s mode of action via direct binding to its target may in part explain the lack of resistance evolution observed to the drugthere are severe fungal fitness tradeoffs between this resistance and virulence6. At the same time, AmB binds cholesterol as well as
ergosterol, most likely explaining its host toxicity7. Is it possible to decouple these factors and have an AmB that is less toxic but still retains its effectiveness? Hints of this possibility were identified in some allosteric properties of AmB. The authors OH
Me
OH
O
OH
C13
HO
Me
O
OH
OH
OH
OH
C16
O
O
Me O
O C3
C2
AmB
OH
OH Me HO
OH
OH
O Me
Me OH NH2
OH O
O
OH
OH
OH
OH
O
N H
N H
Me
Me O AmBMU
OH
OH Me HO
OH
O Me
Me OH NH2
O
OH O
O
OH
OH
OH
OH
O
N H
N H
NH2
Me O AmBAU
O OH
Me OH NH2
Figure 1 | The chemical structures of AmB and the urea derivatives. AmB methyl urea (AmBMU) and AmB amino urea (AmBAU) were developed by making them less able to act as a known ‘sterol sponge’ mechanism of AmB toward cholesterol (while still targeting ergosterol), and these still evade resistance. The modified C16 carboxyl position is depicted in blue, and the C3 methyl and the derivative ureas are in red.
nature chemical biology | Advance online publication | www.nature.com/naturechemicalbiology
1
news & views hypothesized that two polar interactions between the mycosamine appendage and the main carbon backbone of the molecule were responsible for its coaffinity with both cholesterol and ergosterol: a water bridge between the mycosamine C2 and C13 hydroxyl groups and a salt bridge between the mycosamine C3 amino group and the backbone C16 carboxyl. The work that proved this used a new ergosterol-specific AmB derivative dehydroxylated in the C2 of its mycosamine appendage, disrupting the water bridge7; however, synthesis of this form was not practical for large-scale production. The authors then focused on the C3 amino–C16 carboxyl interaction and developed a simple three-step synthesis that replaces the C16 carboxyl with various urea-derived forms. In vitro experiments using these AmB ureas demonstrated a lack of resistance evolution with much lower toxicity. This promising set of compounds (Fig. 1) should lead to new tools for the aggressive treatment of fungal infections,
2
without the terrible side effects that have given AmB its bad reputation. Even within the confines of a very limited set of functional targets, antifungal treatments have improved greatly in the last two decades. Liposomal preparations of AmB have permitted more targeted treatment, with reduced side effects. The use of triazoles, which are less toxic than AmB, has proven effective across a wide range of serious invasive infections, in many cases replacing its use. And new antifungal modes of action are being discovered, such as that mediated by oxaborole compounds, that may eventually be used to treat invasive infections. A less toxic version of AmB that is just as effective and not prone to the evolution of resistance would represent another major step forward in the improvement of the antifungal arsenal. Furthermore, the functional and biological approach used to identify these compounds can be applied to AmB for further refinement and for diverse
applications in fighting fungal infections in medicine and perhaps even in agriculture. ■ David M. Geiser is in the Department of Plant Pathology and Environmental Microbiology at Pennsylvania State University, University Park, Pennsylvania, USA. e-mail: [email protected] Published online 1 June 2015 doi:10.1038/nchembio.1838 References
1. Pappas, P.G. et al. Clin. Infect. Dis. 48, 503–535 (2009). 2. Walsh, T.J. et al. Clin. Infect. Dis. 46, 327–360 (2008). 3. Davis, S.A. et al. Nat. Chem. Biol. doi:10.1038/nchembio.1821 (1 June 2015). 4. Gray, K.C. et al. Proc. Natl. Acad. Sci. USA 109, 2234–2239 (2012). 5. Anderson, T.M. et al. Nat. Chem. Biol. 10, 400–406 (2014). 6. Vincent, B.M., Lancaster, A.K., Scherz-Shouval, R., Whitesell, L. & Lindquist, S. PLoS Biol. 11, e1001692 (2013). 7. Wilcock, B.C., Endo, M.M., Uno, B.E. & Burke, M.D. J. Am. Chem. Soc. 135, 8488–8491 (2013).
Competing financial interests The author declares no competing financial interests.
nature chemical biology | Advance online publication | www.nature.com/naturechemicalbiology
