Does Growth Efficiency Determine the Inoculum Effect?

Principal Investigator/Project Director

Robert Smith

Colleges / Centers

Halmos College of Arts and Sciences

Funder

NIH

Start Date

12-2021

Abstract

As we enter the post antibiotic era, antibiotic resistant bacteria pose one of the greatest challenges to public health. A lack of development of new antibiotics has created a need to develop strategies to augment and extend the efficacy of existing antibiotics. Infections are not often comprised of a single species of bacteria but instead consist of multiple bacterial species comprising a polymicrobial community. These communities are more complex to treat resulting in longer hospital stays and reduced patient outcomes. One polymicrobial community that is of increasing concern in the clinic is composed of Pseudomonas aeruginosa and Staphylococcus aureus. When grown together, these two species interact, which increases virulence and antibiotic tolerance. In the latter, small molecules produced by P. aeruginosa reduce the metabolism of S. aureus, which forces it into an antibiotic tolerant state. Together, this reduces antibiotic effectiveness and prolongs healing times. However, it has been recently discovered that we can alter the ability of bacteria to tolerate antibiotic treatment by manipulating their metabolism; increasing bacterial metabolism increases antibiotic susceptibility. This discovery holds tremendous promise for the development of antibiotic adjuvants that potentiate metabolism and antibiotic lethality. However, most studies that have examined antibiotic tolerance and metabolism have not considered how providing adjuvants in the form of metabolism potentiating metabolites might affect the virulence and antibiotic tolerance of polymicrobial infections. On the one hand, and in the case of infections caused by S. aureus and P. aeruginosa, the use of antibiotics and metabolite adjuvants might increase, and not reduce, the virulence and tolerance of the community. On the other, if we can identify metabolites that decrease virulence and antibiotic tolerance of this polymicrobial community, then we can use these metabolites augment treatment efficacy. Thus, it is important that we understand how metabolites affect virulence and antibiotic tolerance in this polymicrobial community. To initiate an understanding of how metabolites affect the antibiotic tolerance and virulence of this polymicrobial community, in this proposal we ask: “Can we rationally manipulate the virulence and antibiotic susceptibility of S. aureus and P. aeruginosa when in co-culture using metabolites?” To address this question, we propose two specific aims. First, using a combination of experimentation and mathematical modeling, we will investigate how metabolites that are known to differentially affect metabolism in S. aureus and P. aeruginosa in monoculture affect the production of virulence factors and interspecies interactions when these bacteria are grown in coculture. Results from this aim will allow us to identify metabolites that reduces the virulence of this polymicrobial community, which may help to increase healing times in the clinic. Second, using a combination of mathematical modeling and experimentation, we will investigate how different metabolites affect antibiotic tolerance of this polymicrobial community. Results will identify metabolites that allow the polymicrobial community to be eliminated at lower amounts of antibiotics, which will extend the ‘shelf life’ of existing antibiotics.

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