Discovery of Antibacterial Contezolid Acefosamil: Innovative <i>O</i>-Acyl Phosphoramidate Prodrug for IV and Oral Therapies

Liu, Jinqian; Wang, Wen; Zhang, Li; Zhang, Xueliang; Liu, Shicong; Xu, Yunhua; Wang, Hailin; Dai, Qionghai; Li, Chun; Wang, Xinghai; Yuan, Zhengqiu; Gordeev, M. F.

doi:10.1021/acsmedchemlett.2c00191

Cited by 13 publications

(5 citation statements)

References 17 publications

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“…It was approved by the Chinese National Medical Products Administration (NMPA) in June 2021 for the treatment of complicated skin and soft tissue infections (cSSTI), including, but not limited to, MSSA, MRSA, Streptococcus pyogenes and Streptococcus agalactiae [46][47][48]. The development pathway from contezolid (4) [49] to contezolid acefosamil (3) (MRX-4) was recently published [50]. The prodrug 3 provides dramatic improvements in solubility over the parent antibiotic (from 0.2 mg ml −1 to >200 mg ml −1 ), leading to exposure of contezolid (4) in rats after IV administration of contezolid acefosamil (3) like, or higher than, that from direct IV administration of 4.…”

Section: Antibacterial Drugs Launched From January 2013 To December 2022mentioning

confidence: 99%

Antibiotics in the clinical pipeline as of December 2022

et al. 2023

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The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed.

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Section: Antibacterial Drugs Launched From January 2013 To December 2022mentioning

confidence: 99%

Antibiotics in the clinical pipeline as of December 2022

et al. 2023

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“…21 Furthermore, Contezolid acefosamil, the prodrug of contezolid, exhibited reduced MAO inhibition-induced 5-hydroxytryptamine (5-HT) neurotoxicity and improved water solubility, with comparable antibacterial activity and higher safety compared to linezolid. 40 Another compound, WCK4034 (6), exhibited equal in vitro activity as linezolid against MSSA and MRSA while showing better in vivo activity than linezolid with an ED 50 value of 2.5 mg/kg, whereas linezolid showed ED 50 values ranging from 2.5 to 5 mg/kg. 41 The bioisosteric replacement strategy is instrumental in developing novel oxazolidinone antibiotics.…”

Section: Development Of Oxazolidinones As Antibacterial Agents Using ...mentioning

confidence: 99%

Strategies for the Discovery of Oxazolidinone Antibacterial Agents: Development and Future Perspectives

Liu,

Jiang,

Jiao

et al. 2023

J. Med. Chem.

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Oxazolidinones represent a significant class of synthetic bacterial protein synthesis inhibitors that are primarily effective against Gram-positive bacteria. The commercial success of linezolid, the first FDA-approved oxazolidinone antibiotic, has motivated researchers to develop more potent oxazolidinones by employing various drug development strategies to fight against antimicrobial resistance, some of which have shown promising results. Thus, this Perspective aims to discuss the strategies employed in constructing oxazolidinone-based antibacterial agents and summarize recent advances in discovering oxazolidinone antibiotics to provide valuable insights for potentially developing next-generation oxazolidinone antibacterial agents or other pharmaceuticals.

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“…Due to its modest solubility, CZD usage is limited to oral (PO) administration. Novel oxazolidinone agent contezolid acefosamil (CZA), an IV prodrug of CZD, was created to address the solubility issue of oral CZD (Liu et al, 2022). CZA exhibits high aqueous solubility in excess of 200 mg/mL and is bioavailable through both IV and PO administrations.…”

Section: Introductionmentioning

confidence: 99%

“…Structurally, CZA is an O ‐acyl phosphoramidate, a double prodrug of CZD (Liu et al, 2022). As illustrated in Scheme 1, upon administration, CZA is rapidly metabolized into deacylated phosphoramidate MRX‐1352.…”

Section: Introductionmentioning

confidence: 99%

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

Wang,

Li,

Gordeev

et al. 2024

J of Applied Toxicology

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Contezolid acefosamil (CZA) is an intravenous prodrug of oxazolidinone antibiotic contezolid (CZD). It is being developed to treat infections due to Gram‐positive bacteria including multidrug‐resistant pathogens, while addressing myelosuppression and neurotoxicity limitations associated with long‐term use of this class of antibiotics. In vivo, CZA is rapidly deacylated into its first metabolite MRX‐1352, which is then dephosphorylated to release active drug CZD. Four‐week repeat‐dose toxicity studies of intravenous CZA were conducted in Sprague–Dawley rats (40, 80, and 160/120 mg/kg/dose twice a day [BID]) and beagle dogs (25, 50, and 100/75 mg/kg/dose BID). The high doses administered to both rats and dogs were adjusted due to adverse effects including decreased body weight and food consumption. Additionally, a dose‐dependent transient reduction in erythrocyte levels was recorded at the end of dosing phase. Importantly, no myelosuppressive reduction in platelet counts was observed, in contrast to the myelosuppression documented for standard‐of‐care oxazolidinone linezolid. The no‐observed‐adverse‐effect level (NOAEL) of CZA was 80 and 25 mg/kg/dose BID in rats and dogs, respectively. Separately, 3‐month neuropathological evaluation in Long–Evans rats (25, 37.5, and 50 mg/kg/dose, oral CZA, BID) demonstrated no neurotoxicity in the central, peripheral, and optical neurological systems. Toxicokinetic data from these studies revealed that CZD exposures at NOAELs were higher than or comparable with that for the intended clinical dose. These results confirm the favorable safety profile for CZA and support its clinical evaluation for long‐term therapy of persistent Gram‐positive infections, beyond the application for earlier oxazolidinones.

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Discovery of Antibacterial Contezolid Acefosamil: Innovative O-Acyl Phosphoramidate Prodrug for IV and Oral Therapies

Cited by 13 publications

References 17 publications

Antibiotics in the clinical pipeline as of December 2022

Antibiotics in the clinical pipeline as of December 2022

Strategies for the Discovery of Oxazolidinone Antibacterial Agents: Development and Future Perspectives

Preclinical toxicity evaluation of novel antibacterial contezolid acefosamil in rats and dogs

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