Identification of a small molecule inhibitor of virulence factors in multidrug resistant acinetobacter baumannii
Massey, George David Kostides
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Acinetobacter baumannii is an opportunistic pathogen prevalent in nosocomial infections, most commonly infecting humans with compromised immune systems during their hospital stays. The organism's success in such circumstances has to do with its ability to survive on dry, abiotic surfaces (e.g. catheters, bed railings, and other medical equipment) and its increasingly apparent antibiotic resistance. These factors make A. baumannii a serious problem for healthcare professionals and in public health generally. A. baumannii is paradigmatic and representative of the issues confronting healthcare in the ongoing antibiotic crisis, and many strains are showing multidrug resistant (MDR) phenotypes. Given that the patients infected by A. baumannii tend to be very vulnerable and traditional antibiotic treatment seems to be getting less and less effective, it is imperative to explore alternative treatment options that may lead to better outcomes, especially if their mechanisms are not the same as the traditional antibiotics that exert the selective pressures that have led to the current antibiotic crisis. A small molecule called M64 is known to inhibit a LysR-type transcription regulator (LTTR) important for virulence, but not cell growth or viability, in another opportunistic pathogen, Pseudomonas aeruginosa. The experiments presented here show that M64 was able to rescue mice infected with A. baumannii and to downregulate the expression of important metabolic genes downstream from A. baumannii LTTRs BenM and CatM in vitro while having no effect on bacterial growth. BenM and CatM regulate genes involved in the metabolism of benzoate and catechol respectively, both of which are parts of tryptophan metabolism and are eventually broken down to form acetyl-CoA and succinyl-CoA for energy production in the citric acid cycle. Such a pharmacodynamic profile offers a starting point in the design of alternative treatments of MDR bacterial infections, as successful outcomes are observed without the direct killing of cells in vitro seen in traditional antibiotics. In this case, as catechol metabolism is important for siderophore biosynthesis and thus bacterial virulence, inhibition of the transcription of genes involved in catechol metabolism may be playing a role in the observed rescue of infected mice. Further studies are required to ascertain the nature of the inhibitor's effect, however.