Brian Conlon, PhD

Research

Antibiotic tolerance and antibiotic resistance are major challenges, resulting in growing numbers of deaths worldwide each year. The Conlon Lab focuses on antibiotic tolerance and resistance in the infection microenvironment. Here, nutrient availability, interactions between the pathogen and the host, as well as co-infecting or commensal microorganisms can have a major impact on antibiotic tolerance and the evolution of antibiotic resistance. Using mice to model numerous infection types including a diabetic wound, a skin and soft tissue infection and bacteremia, we aim to identify drivers of antibiotic success or failure, with a focus on one of the most important human pathogens, Staphylococcus aureus. Developing an understanding of the determinants of treatment success or failure then facilitates translational projects to augment the microenvironment, improve antibiotic efficacy and eradicate infection.

We are also interested in the development of novel approaches to target and kill bacteria that have entered a low metabolic state, for example, S. aureus within a biofilm.

Our long-term goal is to develop a thorough understanding of how S. aureus survives antibiotic treatments during infection and to develop novel antibiotic treatments to efficiently kill this pathogen and improve the treatment chronic and relapsing infections.

Our research can be divided into 2 major topics:

 1. The role of the innate immune system in the failure of antibiotic treatments

The impact of various components of the innate immune response on antibiotic efficacy in patients remains largely unknown. We find that in murine bacteremia, large reservoirs of S. aureus can survive antibiotic treatment in a variety of tissues. We also find that this survival is induced, at least in part, by host produced reactive oxygen species (ROS) that inhibit bacterial central metabolism and induce an antibiotic tolerant state. We further find that reducing ROS by genetic manipulation of the mice or application of an antioxidant results in improved antibiotic efficacy, thereby demonstrating that ROS, a major component of the innate immune response, are antagonistic to antibiotic efficacy in vivo. We aim to further investigate the mechanism of ROS induced tolerance while examining the feasibility of developing new host-targeted therapeutics to restore antibiotic susceptibility during infection. We are also interrogating other aspects of S. aureus host interaction that induce an antibiotic tolerant state with a goal towards identifying new therapeutic options to unleash the bactericidal activity of antibiotics during infection.

2. New therapeutic development

We are interested in identifying new ways of directly targeting and killing antibiotic tolerant persister cells for the rapid eradication of S. aureus populations. We have identified numerous methods to kill persister cells and we are continuing to pursue these methods for the development of anti-persister therapeutics, capable of rapidly eradicating S. aureus in vivo. These approaches include the targeting of the membrane to sensitize bacteria to standard of care antibiotics. We believe that developing novel therapeutics to target the antibiotic tolerant state will lead to novel therapeutics capable of more efficiently and effectively treating S. aureus infection.

Our long-term goal is to develop a thorough understanding of how S. aureus survives antibiotic treatments during infection and to develop novel antibiotic treatments to efficiently kill this pathogen and improve the treatment chronic and relapsing infections.

Selected Publications

1. Host stress drives tolerance and persistence: The bane of anti-microbial therapeutics. Helaine S, Conlon BP, Davis KM, Russell DG. Cell Host & Microbe, 32 (6), 852-862, (2024).
2. In-patient evolution of a high-persister Escherichia coli strain with reduced in-vivo antibiotic susceptibility. Parsons JB, Sidders AE, Velez AZ, Hanson BM, Ruffin F, Rowe SE, Arias CA, Fowler VG, Thaden JT, Conlon BP. PNAS, (2024).
3. Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus. Beam JE, Wagner NJ, Lu KY, Rowe SE, Conlon BP,  iScience, 26 (10), (2023).
4.  Antibiotic-induced accumulation of lipid II sensitizes bacteria to antimicrobial fatty acids. Sidders AE, Kedziora KM, Beam JE, Bui D, Parsons JB, Rowe SE, and Conlon BP. eLife, 12, e80246, (2023).
5. Reactive oxygen species induce persister formation during systemic Staphylococcus aureus infection.Rowe SE, Wagner N, Li L, Beam JE, Wilkinson AD, Radlinski LR, Zhang Q, Miao EA and Conlon BP.  Nature Microbiology Feb;5(2):282-290, (2020).
6. Chemical Induction of Aminoglycoside Uptake Overcomes Antibiotic Tolerance and Resistance in Staphylococcus aureus. Radlinski L., Rowe SE., Brzozowski R., Wilkinson A., Huang R., Eswara, P., and Conlon BP. Cell Chemical Biology, S2451-9456(19)30240-5, (2019).
7. Pseudomonas aeruginosa exoproducts determine antibiotic efficacy against Staphylococcus aureus. Radlinski L, Rowe SE, Kartchner L, Maile R, Cairns BA, Vitko NP, Gode CJ, Lachiewicz AM, Wolfgang MC and Conlon BP. PLoS Biology, 15(11) e2003981, (2017).
8. Persister formation in Staphylococcus aureus is associated with ATP depletion. Conlon BP, Rowe SE, Brown-Gandt AV, Nuxoll AS, Clair G, Donegan NP, Adkins JN, Cheung AL, Lewis K. Nature Microbiology. 1, 16051, (2016).
9. A new antibiotic kills pathogens without detectable resistance. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Hughes DE, Epstein S, Jones M, Poullenec K, Steadman V, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K. Nature. 517, 455-459, (2015).
10. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Conlon BP, Nakayasu EN, Fleck LE, LaFleur MD, Isabella VM, Coleman K, Leonard SN, Smith RD, Adkins JN, Lewis K.  Nature. 503, 365-370, (2013).