Mechanism of Eravacycline Resistance in Clinical Enterococcus faecalis Isolates From China

Abstract

Opportunistic infections caused by multidrug-resistant Enterococcus faecalis strains are a significant clinical challenge. Eravacycline (Erava) is a synthetic fluorocycline structurally similar to tigecycline (Tige) that exhibits robust antimicrobial activity against Gram-positive bacteria. This study investigated the in vitro antimicrobial activity and heteroresistance risk of Eravacycline (Erava) in clinical E. faecalis isolates from China along with the mechanism of Erava resistance. A total of 276 non-duplicate E. faecalis isolates were retrospectively collected from a tertiary care hospital in China. Heteroresistance to Erava and the influence of tetracycline (Tet) resistance genes on Erava susceptibility were examined. To clarify the molecular basis for Erava resistance, E. faecalis variants exhibiting Erava-induced resistance were selected under Erava pressure. The relative transcript levels of six candidate genes linked to Erava susceptibility were determined by quantitative reverse-transcription PCR, and their role in Erava resistance and heteroresistance was evaluated by in vitro overexpression experiments. We found that Erava minimum inhibitory concentrations (MICs) against clinical E. faecalis isolates ranged from ≤0.015 to 0.25 mg/l even in strains harboring Tet resistance genes. The detection frequency of Erava heteroresistance in isolates with MICs ≤ 0.06, 0.125, and 0.25 mg/l were 0.43% (1/231), 7.5% (3/40), and 0 (0/5), respectively. No mutations were detected in the 30S ribosomal subunit gene in Erava heteroresistance-derived clones, although mutations in this subunit conferred cross resistance to Tige in Erava-induced resistant E. faecalis. Overexpressing RS00630 (encoding a bone morphogenetic protein family ATP-binding cassette transporter substrate-binding protein) in E. faecalis increased the frequency of Erava and Tige heteroresistance, whereas RS12140, RS06145, and RS06880 overexpression conferred heteroresistance to Tige only. These results indicate that Erava has potent in vitro antimicrobial activity against clinical E. faecalis isolates from China and that Erava heteroresistance can be induced by RS00630 overexpression.

Antimicrobial resistance, biofilm production and invasion of mammary epithelial cells by Enterococcus faecalis and Enterococcus mundtii strains isolated from bovine subclinical mastitis in Brazil

“…Given the increasing number of reports of MDR E. faecalis strains, including those resistant to vancomycin and linezolid (Wen et al . 2020); in this study, multidrug resistance was found in 87·5% of E. faecalis . One strain of E. mundtii (Em41) was resistant to linezolid.…”

“…Vancomycin-resistant enterococci were also reported in dust from pig breeding facilities (15%), wild Eurasian necessary to guarantee consistent safety for consumers (Wu et al 2016). Given the increasing number of reports of MDR E. faecalis strains, including those resistant to vancomycin and linezolid (Wen et al 2020); in this study, multidrug resistance was found in 87Á5% of E. faecalis.…”

Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin

“…Remarkably, an important resistance mechanism for tigecycline relies on mutations of ramR and, consequently, RamA-mediated upregulation of the AcrAB-TolC efflux pump [ 38 , 64 , 65 ]. Further efflux-based mechanisms of resistance towards omadacycline and eravacycline have been recently reported [ 66 , 67 , 68 , 69 ]. Moreover, in the case of resistance development against (fluoro)quinolones or β-lactams such as cefoxitin, mutations in ramR were shown to be the primary and most frequent cause for efflux-mediated MDR phenotypes in species such as Salmonella enterica or K. pneumoniae [ 35 , 70 ].…”

Ribosome Protection Proteins—“New” Players in the Global Arms Race with Antibiotic-Resistant Pathogens

“…The omadacycline (recently approved for clinical use) and eravacycline (currently in phase 3 clinical trials) derivatives of tetracycline are not subjected to Tet-type RPP-mediated ARE. Though the exact reason for this is unknown, it is likely attributed to the novel moieties at the C9 position of these drugs compared to the parent tetracycline [59,72,73]. The observation that there are several other tetracycline derivatives in phase 1 of the current pharmaceutical pipeline (Table 3) suggests an increased interest in developing this class of AB to target the clinically relevant MDR pathogens.…”