FRIDAY, 26 JUNE 2020Historically, antibiotic resistance has been a major problem when developing new antibiotics. This is because low levels of resistance against newly discovered antibiotics already exist in the environment, due to the use of soil-dwelling microorganisms that produce antibacterial compounds as a source of antibiotics: the bacteria have already had millennia of exposure to these same compounds and thus the opportunity to co-evolve defences. When coupled with the ability of bacteria to transfer genetic material between species, as well as their relatively rapid mutation rates, it is only a matter of time between the discovery of a new antibiotic and the development and spread of resistance against it.
To avoid this issue, the Princeton team used an alternative approach to find antibiotics, similar to that used to discover the first synthetic antibacterial (sulfonamide): they screened a list of synthetic molecules on the basis of their ability to inhibit the growth of E. coli. One of the compounds they discovered, SCH-79797, demonstrated the ability to inhibit other Gram-positive and Gram-negative bacteria. This broad efficacy is significant because Gram-negative bacteria tend to be more resistant to antibiotics, due to differences in the composition of their cell wall. Interestingly, exposure to sublethal levels of the compound did not provoke resistance, and neither did selecting for resistant strains by repeatedly culturing bacteria that survived a sublethal dose of it. More importantly, the bacteria remained susceptible to the antibiotic even after developing resistance to other antibiotics under similar conditions.
What gives this compound this peculiar feature is unclear, but several possibilities are explored. One possibility is its apparent behaviour as a pore forming toxin targeted to the lipids in the bacterial plasma membrane. Usually, compounds that bind to lipids in the plasma membrane are peptide based, so resistance to them involves proteolytic (protein destroying) degradation. When proteolytic degradation cannot be performed, as is the case with certain antibiotics such as teixobactin and with this new compound, then bacteria simply fail to develop resistance against it. Moreover, the authors were able to increase the compound's selectivity for bacterial cells by 2-3 orders of magnitude by increasing its lipid solubility.
Discoveries like this hint at a whole new class of 'superantibiotics' against which bacteria lack any intrinsic resistance, and for which the development of resistance is costly enough in evolutionary terms to ensure that it does not develop for a sufficiently long period of time.
Paper: Martin et. al. (2020) A dual-mechanism antibiotic targets Gram-negative bacteria and avoids drug resistance. bioRxiv 2020.03.12.984229; DOI: 10.1101/2020.03.12.984229
Clifford Sia is a medical student at the University of Cambridge.