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

Abstract

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.

Contezolid: First Approval

“…At the expected clinically therapeutic exposure level, contezolid did not significantly inhibit MAO in vitro or in vivo [ 4 ]. Moreover, compared with linezolid (which binds to and inhibits both the A and B isoforms of MAO and is thus associated with serotonin syndrome, particularly when coadministered with selective serotonin reuptake inhibitors, tricyclic antidepressants or other MAO inhibitors), contezolid exhibited an ≈ 2- and ≈ 148-fold reduction in MAO-A and -B isoform inhibition in vitro [ 6 ]. The considerable reduction in MAO-B isoform inhibition with contezolid versus linezolid may be clinically relevant, as MAO-B isoform inhibition with linezolid has been associated with neuropathic adverse events [ 6 ].…”

“…Moreover, compared with linezolid (which binds to and inhibits both the A and B isoforms of MAO and is thus associated with serotonin syndrome, particularly when coadministered with selective serotonin reuptake inhibitors, tricyclic antidepressants or other MAO inhibitors), contezolid exhibited an ≈ 2- and ≈ 148-fold reduction in MAO-A and -B isoform inhibition in vitro [ 6 ]. The considerable reduction in MAO-B isoform inhibition with contezolid versus linezolid may be clinically relevant, as MAO-B isoform inhibition with linezolid has been associated with neuropathic adverse events [ 6 ].

Chemical structure of contezolid

MAO inhibition, and thus a drug interaction associated with this inhibition is predicted to be very unlikely with the concomitant administration of contezolid and an MAO substrate (i.e.…”

“…Contezolid 康替唑胺 (Youxitai 优喜泰 ® ) is an orally administered oxazolidinone antibacterial agent being developed by Shanghai MicuRx Pharmaceutical Co., Ltd. for the treatment of MDR Gram-positive bacterial infections, including methicillin-resistant (MR) Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci [ 2 – 5 ]. It was rationally designed to address the myelosuppression and monoamine oxidase (MAO) inhibition limitations associated with linezolid [ 6 ]. On 1 June 2021, contezolid was approved by the National Medical Products Administration of China for the treatment of complicated skin and soft tissue infections (cSSTI), including methicillin-susceptible S. aureus (MSSA), MRSA, Streptococcus pyogenes and Streptococcus agalactiae [ 2 – 4 ].…”

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

“…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.…”

Drug Discovery for Mycobacterium tuberculosis Using Structure-Based Computer-Aided Drug Design Approach

“…Contezolid is currently in phase 3 clinical study and its intravenous administration is facilitated by the introduction of its water-soluble prodrug called contezolid acefosamil [70,87], which has no appreciable antimicrobial activity. The in vitro activity of contezolid against resistance Mtb is related to that of linezolid [71,88].…”