The arsenal of defenses bacteria use to neutralize antibiotics seems to grow larger the more researcher train their microscopes on them. Enzymes. Pumps. Binding proteins. Biofilms. You can add outer membrane vesicles (OMV) to the list. Think of them as antibiotic interceptors. Imperial College London’s Dr. Andrew Edwards discussed his research on OMVs with us.

SCIENTIFIC INQUIRER: When did scientists begin exploring the possibility that bacteria possessed other methods of surviving exposure to antibiotics?

ANDREW EDWARDS: The rise of antibiotic resistance is a long time in the making and threatens to compromise many areas of modern medicine. However, it’s been known for a long time that antibiotics aren’t always effective, even when the infection is caused by a drug-susceptible strain. Therefore, researchers have been trying to understand the basis for antibiotic treatment failure for a long time, although efforts have intensified in recent years. We now know that, in addition to resistance, bacteria can survive antibiotics by becoming dormant (akin to hibernation), by huddling together in big masses (biofilms) that have reduced susceptibility to antibiotics, by hiding in the cells of the host and by releasing antibiotic interceptors that inactivate antibiotics in the extracellular space before they can target the bacteria.

SI: Are some of these strategies employed by bacteria — such as the deployment of outer membrane vesicles — natural processes or are they traits that have been acquired as a result of evolutionary pressure exerted by antibiotics? For example, E. coli releasing OMVs even when they are not under stress.

AE: Many antibiotic interceptors have other functions. For example, extracellular DNA helps to hold biofilms together, whilst outer-membrane vesicles have been implicated in virulence, inter-bacterial signalling and resistance to phages. Therefore, it’s unlikely that they evolved as a direct consequence of antibiotic pressure. However, it’s likely that the presence of antibiotic-producing bacteria in the environment have provided the selection pressure for the maintenance of these systems and/or their adaptation as mediators of antibiotic inactivation. For example, bacteria can package beta-lactamases inside OMVs so that penicillin-type antibiotics can be inactivated before they come into contact with the bacterium.

By contrast, some interceptors have no known function besides antibiotic inactivation. For example, the release of monomeric phospholipids in response to daptomycin, doesn’t occur normally without antibiotic stress.

SI: What is the relation between antibiotic receptors and biofilms? eDNA is the obvious example and is closely linked to biofilms. What about others? Do they play roles in biofilm formation or maintaining biofilms?

AE: Biofilms are clusters of bacteria encased in a matrix of carbohydrate, protein and extracellular DNA (eDNA). These are structural components that hold the bacteria together and protect them from e.g. immune cells. However, there is also evidence that some of these components, particular carbohydrates and DNA are able to trap antibiotics and prevent them from targeting the bacteria in the biofilm.

SI: Considering what is already known about interceptors, what is the biggest question mark that needs to be addressed? Why is it significant?

AE: There are three big questions: how are antibiotics detected by the bacteria? What are the process involved in the manufacture and release of the interceptors? How are these processes regulated?

This is important because if we can understand how the process is controlled, and which genes/proteins are needed for the release of the interceptors then we can design strategies to prevent antibiotic interception (e.g. inhibitors of important proteins and genes). This will make current antibiotics more effective. For example, we have evidence that shutting down daptomycin-induced phospholipid release makes daptomycin work better.

SI: What does all this mean for the fight against antibiotic resistance?

AE: There’s a growing appreciation that bacteria have evolved many strategies to survive exposure to antibiotics, in addition to the established resistance mechanisms of target modification, drug degradation and efflux. Importantly, many of these antibiotic interception strategies would not be detected by current clinical susceptibility tests, perhaps explaining why there is a discord between resistance being rare and treatment failure being frequent for some antibiotics. This suggests that we may need new better tests to detect this novel type of resistance.

On a more positive note, understanding the nature of this problem gives us some targets to aim at to make our current arsenal of antibiotics work better.


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