Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus

Abstract

Background MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem. Objective Idarubicin was profiled to assess its antimicrobial effects in vitro and in vivo , and the underlying mechanisms. Methods We investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects were studied by transmission electron microscopy, all-atom molecular dynamic simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. Further, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection in vivo . Results Idarubicin kills MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects. Conclusions Idarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.

Evaluation of potential anti-RNA-dependent RNA polymerase (RdRP) drugs against the newly emerged model of COVID-19 RdRP using computational methods

“…IDR is a member of the anthracycline antibiotic family, which is usually used for the treatment of acute myeloid leukemia [ 53 ]. It has been reported that IDR can interrupt the DNA topoisomerase IIA subunits [ 54 ] and effectively block the viral protein and RNA synthesis [ 55 ]. Charak and Mehrotra, using UV–visible spectroscopy, observed that IDR gets intercalated between the DNA bases [ 56 ].…”

Repurposing Antispasmodic Agent Otilonium Bromide for Treatment of Staphylococcus aureus Infections

“…Classification criteria: FICI ≤ 0.5 is synergistic; 0.5 < FICI ≤ 1 is additive; 1 < FICI ≤ 4 is irrelevant; >4 is antagonistic (Pengfei et al, 2020).…”

Antimicrobial, Antibiofilm, and Anti-persister Activities of Penfluridol Against Staphylococcus aureus

“…Pseudomonas aeruginosa PAO1 was supplied by Qiao Minqiang (College of Life Sciences of Nankai University, Tianjin, China). Other clinical isolates strains were obtained from the Third Xiangya Hospital of Central South University (Changsha, China; She et al, 2020 ). Staphylococcus epidermidis and S. aureus were cultured in soybean trypsin broth (TSB; Solarbio, Shanghai, China).…”

“…Staphylococcus aureus was cultured to mid-log growth phase at 37°C, 180 rpm, suspended in PBS, and treated with PF of 8× MIC for 1 h; bacteria without drug treatment served as controls. Bacteria were harvested by centrifugation at 4,000 × g for 5 min and observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM; HITACHI, Tokyo, Japan; She et al, 2020 ).…”