Antibiotic resistance is certainly more of a rule than a question and one which I have discussed several times. The relatively simple genetic structure of bacterial and fungal pathogens and their fast population turnover rate make resistance mutations both likely and common. So it should be exceptional to find a drug that is resistant to such resistance. And that’s exactly the kind of drug Amphotericin B seems to be.

was discovered in 1955 and extracted from the bacteria Streptomyces nodosus, which was originally found in a Venezuelan riverbed. Amazingly, in its nearly 55 years of use, it has generated relatively few resistant pathogens. That’s contrasted with the usual fate of other antibiotics which seem to have an ever decreasing efficacious life-span. For instance, the antifungal drug Fucytosine was introduced in the early 1960’s and saw resistance in strains of Candida in less than 20 years. In fact, it’s estimated that up to 50% of all Candida specimens isolated from new patients are already resistant to Fucytosine. So what makes Amphotericin B so resilient in the face of such odds? Well, there are lots of theories.

For instance, Amphotericin B targets lipids and not proteins. So therefore, it might not be as susceptible to genetic substitutions in drug-binding pockets which is common in drugs that do target proteins. Additionally, Amphotericin B targets the plasma membrane, so it might not be susceptible to resistance through increased drug efflux. Also, Amphotericin B is typically administered intravenously and for short time frames. So it might not be as susceptible as more typical, oral antibiotics that offer greater chance of resistance through their extended treatment periods.

However, Susan Lindquist’s group from MIT believed there might be something more. Wanting to finally piece together the remarkable puzzle of this anti-resistance, the group spent considerable time sequencing the full genome of several rare varieties of AmB-resistant Candida patient specimens that they could find, some evolved, resistant strains grown in the lab and some targeted, site-directed resistant strains created through recombination. They found that the most common sources of genetic resistance derived from mutations in the ERG2, ERG3, ERG6 and ERG11 loci. They also discovered that AmB resistant mutants depends critically on the Hsp90 chaperon protein (similar to that previously seen with Fluconazole resistant strains), and that even small inhibitions of Hsp90 eliminated inherent AmB resistance (Hsp90 is a protein which helps promote the proper folding of other proteins and stabilizes them from heat stress). Since Hsp90 is key in the stabilization of a number of proteins required for tumor growth, Hsp90-inhibitors are also popular in anti-cancer investigations.

Perhaps the most surprising part for Lindquist’s group though, was that the Hsp90 inhibitors completely blocked all growth of AmB resistant strains all by themselves, even in the absence of AmB and was effectively cytocidal! This would suggest that, contrary to mutations in other fungicidal resistant strains, the growth of AmB mutant strains rely on a critical level of Hsp90 just to survive. It would also seem that these resistant-mutant strains are simply doomed from the beginning. In effect, the act of becoming resistant to Amphotericin B makes them susceptible to a host of other, normal immunological responses and all but renders them avirulent.

So even though the point of this study was to discover the mechanism of anti-resistance in Amphotericin B, the bigger story is likely the position that Hsp90 plays in the enabling of new mutations and phenotypes to survive. Even more, this finding shines a light on the prospect of treating resistant strains with chemicals that antagonize and exploit the resistance mechanism. As fungal infections often turn deadly in the face of immuno-compromised cancer treatment and are cause for nearly as many deaths as the cancers themselves, this might be a path of investigation worth traveling.

Vincent, B. M., Lancaster, A. K., Scherz-Shouval, R., Whitesell, L., & Lindquist, S. (2013). Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B. PLoS Biology, 11(10), e1001692.

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