Mechanisms of antibiotic resistance in Staphylococcus aureus
Staphylococcus aureus is the causative agent of numerous chronic and difficult to treat infections, including osteomyelitis (infection of bone), endocarditis (infection of the inner lining of the heart), infections of indwelling devices and cystic fibrosis lung infection. Even when resistance to an antibiotic is not observed, these infections respond poorly to treatment and often require surgical intervention. This is due to the ability of S. aureus to tolerate antibiotics, even at high concentrations. Tolerance is distinct from resistance as it is typically not genetically encoded, and the cells cannot grow in the presence of the antibiotic. Rather, a cell’s behavior, or phenotypic state, allows it to survive in high concentrations of antibiotics for extended periods. This can lead to relapse of infection once antibiotic treatment is ceased. Recent work has shown that low adenosine-triphosphate (ATP, the major energy currency of the cell) leads to antibiotic tolerance of S. aureus in vitro.
Our goal is to determine how various factors in the infection environment can induce antibiotic tolerance in S. aureus and how this can impact the outcome of antibiotic treatment of infections. We use advanced methods such as Tn-seq and single cell analysis to determine the antibiotic tolerance of sub-populations in vitro and during infection. A thorough understanding of tolerance to antibiotics within the host is necessary to facilitate the improvement of treatment of chronic infection.
We are particularly interested in S. aureus in the cystic fibrosis lung. These infections often respond poorly to antibiotics. We are keen to understand the phenotypic state of the bacteria during the infection and how this relates to antibiotic tolerance. Osteomyelitis and endocarditis are other diseases of interest. Both of these infections are difficult to treat with antibiotics and surgical intervention is usually required. Little is known about S. aureus antibiotic tolerance during these infections. A more thorough understanding will lead to improved antibiotic treatments.
We are also interested in the identification of novel compounds that can kill cells exhibiting tolerance to other antibiotics. Previous work on an acyldepsipeptide antibiotic, ADEP4, found that ATP independent activation of the ClpP protease can eradicate antibiotic tolerant populations in vitro and in a deep-seated infection in a mouse. In collaboration with medicinal chemists, we will establish screens to identify new compounds with activity against tolerant populations. Upon identification of such a compound, we will identify the mechanism of action and initiate medicinal chemistry optimization projects.
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.
Conlon Lab Team
Shan Y, Brown Gandt A, Rowe SE, Deisinger JP, Conlon BP, Lewis K. ATP-dependent persister formation in Escherichia coli. mBio (2017).
Waters EM, Rowe SE, O’Gara JP, Conlon BP. Convergence of Staphylococcus aureus persister and biofilm research: Can biofilms be defined as communities of adherent persister cells? PLos Pathogens. (2016)
Homma T, Nuxoll A, Brown AV, Ebner P, Engels I, Schneider T, Götz F, Lewis K, Conlon BP. Dual targeting of cell wall precursors by teixobactin leads to cell lysis. Antimicrobial Agents & Chemotherapy (2016)
Conlon BP, Rowe SE, Brown AV, Nuxoll AS, Donegan NP, Zalis E, Clair G, Adkins JN, Cheung AL, Lewis K. Persister formation in Staphylococcus aureus is associated with ATP depletion. Nature Microbiology (2016)
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. Killing of pathogens by teixobactin without associated resistance. Nature (2015).
Conlon BP, Nakayasu EN, Fleck LE, LaFleur MD, Isabella VM, Coleman K, Leonard SN, Smith RD, Adkins JN, Lewis K. Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature. 503, 365-370, (2013).