Increasing resistance to antibiotics in gram-positive cocci is a major concern of health care. In particular, the emergence of multidrug-resistant (MDR) bacteria leads to a decline in the treatment options. The World Health Organization (WHO) published a list of antibiotic-resistant “priority pathogens” in 2017 (Asokan et al., 2019). Among these pathogens, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) are of particular concern since they are responsible for several severe infections. MRSA exhibits resistance to most available antibiotics, including fluoroquinolones and peptides, aminoglycosides, macrolides, and tetracycline (Osei Sekyere and Mensah, 2020). Therefore, novel antibacterial agents are urgently needed to treat infectious diseases caused by MDR gram-positive pathogens.

Oxazolidinones are a class of synthetic antimicrobial agents that are used to treat serious infections caused by gram-positive pathogens, including MRSA and VRE (Zurenko et al., 2001). Linezolid is the first member of the oxazolidinone antibiotics, which has some adverse effects (Hashemian et al., 2018). Clinical utilization of linezolid is restricted due to its toxicity such as myelosuppression and monoamine oxidase inhibition (MAOI) (Zahedi Bialvaei et al., 2017; Lee and Caffrey, 2018). In addition, the prevalence of linezolid resistance is increasing in many countries (Gu et al., 2013). The presence of optrA and cfr genes is one of the mechanisms mediating resistance to linezolid (Sadowy, 2018; Ruiz-Ripa et al., 2020).

Contezolid is a novel ortho-fluoro dihydropyridone oxazolidinone that replaces the morpholine in linezolid with a piperidinone (Meng et al., 2015). Contezolid inhibits the formation of functional 70S initiation complex by binding to the 23S rRNA region adjacent to the peptidyl transferase center of the 50S ribosomal subunit, thereby interfering with bacterial protein synthesis (Shinabarger, 1999). Contezolid has demonstrated potent antibacterial activity against resistant gram-positive pathogens (Gordeev and Yuan, 2014; Li et al., 2014; Wu et al., 2018). Additionally, contezolid showed antibacterial potential in multiple animal models, generally comparable with or slightly better than that for linezolid (Li et al., 2014), coupled with markedly attenuated human bone marrow cytotoxicity (Gordeev and Yuan, 2014; Huang et al., 2014; Li et al., 2014; Eckburg et al., 2017). In a phase III trial conducted in China (CTR20150855), contezolid was in development to treat complicated skin and soft tissue infections (Bassetti et al., 2020). According to the study, the most common adverse events associated with contezolid were gastrointestinal disorders such as nausea, and the incidence of myelosuppression was significantly lower than linezolid. Furthermore, contezolid displays a low propensity of spontaneous resistance (Gordeev and Yuan, 2014), and low potential to trigger resistance in S. aureus (Huang et al., 2014). Consequently, contezolid has the potential of offering a promising alternative therapy for MDR gram-positive organism infections.

The objective of this study was to evaluate the in vitro activity of contezolid relative to that of other comparator antimicrobial agents against MRSA, VRE, and strains carrying linezolid resistance genes using clinical isolates collected from China.

The antibacterial resistance toward currently available antibiotics is a widespread global health crisis. MDR gram-positive bacteria, accounting for both community-acquired and healthcare-associated infections, create numerous clinical challenges (Stevenson et al., 2005; Hoskins et al., 2018). Among them, MRSA and VRE deserve special attention for their high level of drug resistance. Accordingly, the development of new antibiotics is eagerly required to counter resistance.

Contezolid is a new oxazolidinone antibacterial agent with activity against gram-positive bacteria, including some multi-drug resistant organisms, such as MRSA, VRE, and PRSP (Gordeev and Yuan, 2014). Contezolid markedly reduces the potential for myelosuppression and monoamine oxidase inhibition compared to linezolid (Gordeev and Yuan, 2014), which seems to increase the clinical attractiveness of contezolid. Moreover, contezolid was reported to be not inferior to linezolid for the treatment of complicated skin and soft tissue infections with fewer hematology-associated adverse events in a phase three clinical trial conducted in China (Bassetti et al., 2020), indicating similar therapeutic outcomes between contezolid and linezolid. Contezolid acefosamil is the prodrug of the contezolid. In vivo, the double prodrug structure undergoes metabolic degradation including O-deacetylation and N-dephosphorylation, followed by the release of the active drug, contezolid. The prodrug form, which is water-soluble, could be used for either oral or intravenous administration of contezolid (Wang et al., 2021). Contezolid was approved for clinical use in China on July 2, 2021 for the treatment of complicated skin and soft tissue infections. And contezolid has been granted QIDP designation and Fast Track status by the US FDA.

In the present study, contezolid displayed potent activity against the whole collection of MRSA and VRE isolates. The antimicrobial activity of contezolid is comparable to that of linezolid based on MIC₅₀ and MIC₉₀ values. These results are in accordance with previous studies conducted in the United States and Europe (Carvalhaes et al., 2020). Notably, among VRE isolates, isolates with linezolid MIC values ≤0.5 μg/mL were statistically less than that of contezolid (P < 0.001). This indicated that the MIC distributions of contezolid against VRE are better than that of linezolid. Of concern, cross-resistance between linezolid and tedizolid, which both belong to oxazolidinone agents, was reported in staphylococci previously (Barber et al., 2016). In the current study, contezolid exhibited limited activity against strains with linezolid resistance genes. Consequently, the presence of the cfr and optrA genes may result in resistance to contezolid. This indicates that cross-resistance may also exist between contezolid and linezolid, which may limit the clinical application of contezolid. It also suggests the need to strengthen the clinical monitoring of cross-resistance between contezolid and linezolid. Among all the comparator agents tested, contezolid had relatively lower MIC₅₀ and MIC₉₀ values, indicating that its antimicrobial activity against MRSA and VRE was better than some antibiotics. Therefore, contezolid may offer another option for the clinical treatment of MDR gram-positive bacteria.

In summary, contezolid displayed potent in vitro activity against MRSA and VRE isolates collected from China. The antimicrobial activity of contezolid is similar to or slightly better than that of linezolid against MRSA and VRE isolates. However, cross-resistance may exist between contezolid and linezolid. The in vitro data in the current study imply that contezolid may be a promising candidate to treat MRSA and VRE infections, but may not be helpful for infections caused by linezolid-resistant strains. Further experimental and clinical researches are demanded to promote the progress of contezolid to reach clinical practice.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

RZ and HZ designed the study. SW, YS, CS, QS, NW, SZ, and JQ did the experiment. CC, RZ, and HZ analyzed and interpreted the data. SW, HZ, and RZ wrote the manuscript. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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