Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

Background.Vancomycin-resistant enterococci (VRE) cause severe infections among patients with malignancy, and these infections are usually preceded by gastrointestinal colonization.Methods.We searched the PubMed and EMBASE databases (up to May 26, 2016) to identify studies that reported data on VRE gastrointestinal colonization among patients with solid or hematologic malignancy.Results.Thirty-four studies, reporting data on 8391 patients with malignancy, were included in our analysis. The pooled prevalence of VRE colonization in this population was 20% (95% confidence interval [CI], 14%–26%). Among patients with hematologic malignancy, 24% (95% CI, 16%–34%) were colonized with VRE, whereas no studies reported data solely on patients with solid malignancy. Patients with acute leukemia were at higher risk for VRE colonization (risk ratio [RR] = 1.95; 95% CI, 1.17–3.26). Vancomycin use or hospitalization within 3 months were associated with increased colonization risk (RR = 1.92, 95% CI = 1.06–3.45 and RR = 4.68, 95% CI = 1.66–13.21, respectively). Among the different geographic regions, VRE colonization rate was 21% in North America (95% CI, 13%–31%), 20% in Europe (95% CI, 9%–34%), 23% in Asia (95% CI, 13%–38%), and 4% in Oceania (95% CI, 2%–6%). More importantly, colonized patients were 24.15 (95% CI, 10.27–56.79) times more likely to develop a bloodstream infection due to VRE than noncolonized patients.Conclusions.A substantial VRE colonization burden exists among patients with malignancy, and colonization greatly increases the risk for subsequent VRE bloodstream infection. Adherence to antimicrobial stewardship is needed, and a re-evaluation of the use of vancomycin as empiric therapy in this patient population may be warranted.

Chronic Staphylococcus aureus infections are complicated by frequent relapses not only from the development of drug resistance to conventional antibiotics, but also through the formation of persister bacterial cells. Bacterial persisters are in a transient, metabolically inactive state, making conventional antibiotics that target essential cellular growth processes ineffective, resulting in high clinical failure rates of antibiotic chemotherapy. The development of new antibiotics against persistent S. aureus is an urgent issue. Over the last decade, new strategies to identify S. aureus persister-active compounds have been proposed. This review summarizes the proposed targets, antipersister compounds and innovative methods that may augment conventional antibiotics against S. aureus persisters. The reviewed antipersister strategies can be summarized as two broad categories; directly targeting growth-independent targets and potentiating existing, ineffective antibiotics by aiding uptake or accessibility.