Selection and characterisation of Staphylococcus aureus mutants with reduced susceptibility to the investigational oxazolidinone MRX-I

Huang, Yanqin; Xu, Yunhua; Liu, Shicong; Wang, Hailin; Xu, Xiaogang; Guo, Qinglan; Wu, Baixue; Gordeev, M. F.; Wang, Wen; Yuan, Zhengqiu; Wang, Minggui

doi:10.1016/j.ijantimicag.2014.02.008

Cited by 20 publications

(13 citation statements)

References 13 publications

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“…The MIC values of contezolid, as well as those of the other eight drugs listed above, did not increase following contezolid preexposure (see Table S4). Huang and coworkers reported similar results, i.e., contezolid exhibited a lower potential than linezolid to induce mutations and resistance in S. aureus ( 17 ).…”

Section: Contezolid Is Active Against M Abscessusmentioning

confidence: 75%

A Novel Oxazolidinone, Contezolid (MRX-I), Expresses Anti-Mycobacterium abscessus Activity In Vitro

Guo

Tan³

et al. 2021

Antimicrob Agents Chemother

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An evaluation of the anti- M. abscessus activity expressed by a novel oxazolidinone, contezolid (MRX-I), toward 12 reference strains and 194 clinical isolates was conducted. Contezolid was active against M. abscessus in vitro , and comparable to the anti- M. abscessus effects of linezolid both extracellularly and intracellularly. Contezolid did not antagonize the most frequently used anti- M. abscessus drugs nor did pre-exposure to contezolid induce drug resistance. These results provide a novel approach to treating M. abscessus infections.

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Section: Contezolid Is Active Against M Abscessusmentioning

confidence: 75%

A Novel Oxazolidinone, Contezolid (MRX-I), Expresses Anti-Mycobacterium abscessus Activity In Vitro

Guo

Tan³

et al. 2021

Antimicrob Agents Chemother

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“…Contezolid maintains the high antibacterial potency and therapeutic efficacy characteristic of linezolid, while exhibiting a markedly attenuated myelosuppression. 25 In addition, the new agent exhibits a reduced propensity toward developing bacterial resistance 31 as well as an improved potency against some Gram-positive isolates. 25,32 Herein, we describe initial preclinical characterization of the MAO-related safety profile for contezolid and its prodrug form contezolid acefosamil, including in vitro testing for the active drug form, contezolid, as well as in vivo evaluation of serotonergic neurotoxicity and tyramine potentiation profile for contezolid acefosamil in animal models (additional safety data for contezolid were previously reported).…”

Section: Introductionmentioning

confidence: 99%

“…Contezolid maintains the high antibacterial potency and therapeutic efficacy characteristic of linezolid, while exhibiting a markedly attenuated myelosuppression . In addition, the new agent exhibits a reduced propensity toward developing bacterial resistance as well as an improved potency against some Gram-positive isolates. , …”

Section: Introductionmentioning

confidence: 99%

Nonclinical Evaluation of Antibacterial Oxazolidinones Contezolid and Contezolid Acefosamil with Low Serotonergic Neurotoxicity

Wang¹,

Voss

Liu³

et al. 2021

Chem. Res. Toxicol.

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Linezolid, the principal oxazolidinone antibiotic for therapy of Gram-positive infections, is limited by its myelosuppression and monoamine oxidase (MAO) inhibition, with the latter manifested as serotonergic neurotoxicity. The oral oxazolidinone contezolid and its injectable prodrug contezolid acefosamil are developed to overcome the above limitations. Serotonergic profiles for contezolid in vitro and for orally administered contezolid acefosamil in rodents are reported. Contezolid exhibited 2- and 148-fold reduction over linezolid reversible inhibition of MAO-A and MAO-B human enzyme isoforms. In the mouse head-twitch model, contezolid acefosamil was devoid of neurotoxicity at supratherapeutic oral doses of 40, 80, and 120 mg/kg. In the rat tyramine challenge model, no significant increase in arterial blood pressure was observed for contezolid acefosamil up to 120 mg/kg oral dosing. In these tests, the comparator linezolid has elicited serotonergic responses. Thus, contezolid and contezolid acefosamil exhibited an attenuated propensity to induce MAO-related serotonergic neurotoxicity. The data support a continued clinical evaluation of these agents, with potential to expand oxazolidinone therapies to patient populations on concurrent selective serotonin reuptake inhibitor medications or where MAO inhibitors are contraindicated.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

In vitro Activity of Contezolid Against Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus, and Strains With Linezolid Resistance Genes From China

Wang

Cai²,

Shen

et al. 2021

Front. Microbiol.

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Contezolid is a novel oxazolidinone, which exhibits potent activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). In this study, the in vitro activity of contezolid was compared with linezolid (LZD), tigecycline (TGC), teicoplanin (TEC), vancomycin (VA), daptomycin (DAP), and florfenicol (FFC) against MRSA and VRE strains isolated from China. Contezolid revealed considerable activity against MRSA and VRE isolates with MIC90 values of 0.5 and 1.0 μg/mL, respectively. For VRE strains with different resistance genotypes, including vanA- and vanM-type strains, contezolid did not exhibit significantly differential antibacterial activity. Furthermore, the antimicrobial activity of contezolid is similar to or slightly better than that of linezolid against MRSA and VRE strains. Subsequently, the activity of contezolid was tested against strains carrying linezolid resistance genes, including Staphylococcus capitis carrying cfr gene and Enterococcus faecalis carrying optrA gene. The results showed that contezolid exhibited similar antimicrobial efficacy to linezolid against strains with linezolid resistance genes. In general, contezolid may have potential benefits to treat the infections caused by MRSA and VRE pathogens.

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Selection and characterisation of Staphylococcus aureus mutants with reduced susceptibility to the investigational oxazolidinone MRX-I

Cited by 20 publications

References 13 publications

A Novel Oxazolidinone, Contezolid (MRX-I), Expresses Anti-Mycobacterium abscessus Activity In Vitro

A Novel Oxazolidinone, Contezolid (MRX-I), Expresses Anti-Mycobacterium abscessus Activity In Vitro

Nonclinical Evaluation of Antibacterial Oxazolidinones Contezolid and Contezolid Acefosamil with Low Serotonergic Neurotoxicity

In vitro Activity of Contezolid Against Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus, and Strains With Linezolid Resistance Genes From China

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