Biology subjects

Beam, J. E.

Publications and source records attributed to Beam, J. E..

3 recordsLinked to original sources

bioRxiv2022

Antibiotic-induced accumulation of lipid II sensitizes bacteria to antimicrobial fatty acids

Antibiotic tolerance and antibiotic resistance are the two major obstacles to the efficient and reliable treatment of bacterial infections. Identifying antibiotic adjuvants that sensitize resistant and tolerant bacteria to antibiotic killing may lead to the development of superior treatments with improved outcomes. Vancomycin, a lipid II inhibitor, is of major clinical importance for the treatment of Gram-positive bacterial infections. Here we show that unsaturated fatty acids (UFAs) and vancomycin act synergistically to rapidly kill S. aureus, including vancomycin tolerant and resistant populations. Our results suggest that antibiotic-mediated accumulation of lipid II at the septum facilitates membrane invasion by antimicrobial UFAs. UFA-vancomycin dual treatment generates large fluid patches of flexible lipids in the membrane leading to protein delocalization, aberrant septal formation, and loss of membrane integrity. This mechanism of synergy may be exploited for the development of new antibiotic therapies that target lipid II to combat both antibiotic tolerance and resistance.

microbiology↗

bioRxiv2022

Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus

Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. Host-pathogen interactions have been shown to have substantial impacts on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, -toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find -toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance in the host cell cytoplasm. Induction of antibiotic tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.

microbiology↗

bioRxiv2021

Macrophage-produced peroxynitrite induces antibiotic tolerance and supersedes intrinsic mechanisms of persister formation

Staphylococcus aureus is a leading human pathogen that frequently causes chronic and relapsing infections. Antibiotic tolerant persister cells contribute to frequent antibiotic failure in patients. Macrophages represent an important niche during S. aureus bacteremia and recent work has identified a role for oxidative burst in the formation of antibiotic tolerant S. aureus. We find that host-derived peroxynitrite, the reaction product of superoxide and nitric oxide, is the main mediator of antibiotic tolerance in macrophages. Using a collection of S. aureus clinical isolates, we find that, despite significant variation in persister formation in pure culture, all strains were similarly enriched for antibiotic tolerance following internalization by activated macrophages. Our findings suggest that host interaction strongly induces antibiotic tolerance and may negate bacterial mechanisms of persister formation, established in pure culture. These findings emphasize the importance of studying antibiotic tolerance in the context of bacterial interaction with the host suggest that modulation of the host response may represent a viable therapeutic strategy to sensitize S. aureus to antibiotics.

microbiology↗