Abstract
Omadacycline (Omad), a new tetracycline (Tet)-class broad-spectrum aminomethylcycline, has been reported to exhibit excellent potency against Gram-positive bacteria, including Staphylococcus aureus and Enterococci. The aim of this study was to evaluate the in vitro activity and heteroresistance characteristics of Omad in clinical S. aureus isolates from China and investigate Omad resistance mechanisms. A sample of 263 non-duplicate clinical S. aureus isolates [127 methicillin-resistant (MRSA) and 136 methicillin-sensitive (MSSA)] were collected retrospectively. Our data indicated that Omad exhibited excellent in vitro activity against both MRSA and MSSA. Omad heteroresistance frequencies were 3.17% (4/126) in MRSA and 12.78% (17/133) in MSSA. No mutations in Tet target sites, (five 16SrRNA copies and 30S ribosomal protein S10) were present in heteroresistance-derived clones, whereas Tet target site mutations contribute to induced Omad resistance in S. aureus in vitro. RNA sequencing (RNA-Seq) revealed that overexpression of branched-chain amino acid transport system II carrier protein and Na/Pi cotransporter family protein contributes to Omad heteroresistance emergence. Whole-genome sequencing demonstrated that the genetic mutation of fibronectin-binding protein (FnBP) could increase the Omad MIC. In conclusion, Omad heteroresistance risk should be considered in clinical isolates with MICs ≥ 0.5 mg/L and Omad susceptibility in S. aureus may be affected by efflux pump proteins (i.e., a branched-chain amino acid transport system II carrier protein and an Na/Pi cotransporter family protein), and FnBP.
Highlights
Staphylococcus aureus is a pervasive human pathogen that causes infectious diseases ranging in severity from superficial skin abscesses to bacteremia and septic shock (Calfee, 2017)
There were higher frequencies of methicillin-susceptible S. aureus (MSSA) isolates than methicillin-resistant S. aureus (MRSA) isolates with Omad minimum inhibitory concentration (MIC) in the 0.5 and ≥1 mg/L levels
The frequencies of isolates at each Omad MIC level found to be resistant to these antibiotics are reported in Table 1, together with the resistance breakpoints used
Summary
Staphylococcus aureus is a pervasive human pathogen that causes infectious diseases ranging in severity from superficial skin abscesses to bacteremia and septic shock (Calfee, 2017). The incidence of methicillin-resistant S. aureus (MRSA) infection appears to be declining worldwide, the incidence of bacteremia and severe community-acquired infection caused by methicillin-susceptible S. aureus (MSSA) continues to be an important human health threat (Bal et al, 2017) Both MRSA and MSSA infections remain a major clinical problem exacerbated by the ongoing evolution and transmission of traits engendering resistance or reduced susceptibility to current last-line antimicrobial agents, including linezolid, daptomycin, tigecycline (Tig), and vancomycin. Omadacycline [7-dimethylamino, 9-(2,2-dimethylpropyl)-aminomethylcycline; Omad] is a recently developed semisynthetic aminomethylcycline belonging to the tetracycline (Tet) family (Pfaller et al, 2017a) It has extraordinarily broadspectrum antimicrobial activity against Gram-positive and -negative bacteria, including difficult-to-treat multidrug resistant bacteria, such as MRSA and vancomycin-resistant enterococci (Pfaller et al, 2017a). Omad exhibits lower minimum inhibitory concentration (MIC) values against multidrug resistant bacteria than minocycline and Tig (Draper et al, 2014; Honeyman et al, 2015; Heidrich et al, 2016; Villano et al, 2016), making it a novel potential last-resort antibiotic for difficult-to-treat bacteria infections (Noel et al, 2012; Macone et al, 2014; Pfaller et al, 2017b; Zhang et al, 2018)
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