1. Academic Validation
  2. SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae

SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae

  • Antimicrob Agents Chemother. 2024 Jan 10;68(1):e0069523. doi: 10.1128/aac.00695-23.
E B M Breidenstein 1 N Khan 1 T Duffy 1 C Coward 1 T Avis 1 O Abdulle 1 C-M Li 2 C S Mason 1
Affiliations

Affiliations

  • 1 Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom.
  • 2 Summit Therapeutics , Menlo Park, California, USA.
Abstract

Carbapenem-resistant Enterobacteriaceae (CREs) are described by the Centers for Disease Control as an urgent threat, and there is a critical need for new therapeutic agents able to treat infections caused by these pathogens. Herein, we describe the microbiological profile, the mechanism f action, and the in vitro safety as well as the pharmacokinetic (PK)/PD profile of SMT-738, a small molecule belonging to a new chemical class. SMT-738 is active against Enterobacterales [including multi-drug-resistant Escherichia coli with 90% of isolates having a minimum inhibitory concentration (MIC90) of 1 µg/mL and Klebsiella pneumoniae 2 µg/mL] and inactive against a broad panel of Gram-negative and Gram-positive pathogens. SMT-738 displays rapid bactericidal activity (2-4 h) and has a low propensity for resistance development (less than ~10-9). Characterization of resistant mutants following exposure to SMT-738 identified mutations within the lipoprotein transport complex (LolCDE), a clinically unexploited and essential Bacterial molecular target in Gram-negative bacteria. SMT-738 has a promising in vitro toxicology profile. Furthermore, PK studies demonstrated that when dosed intravenously, SMT-738 maintained exposure levels across Infection sites (bloodstream/urinary tract/lung). Proof-of-concept studies across multiple murine in vivo Infection models (bloodstream/pneumonia/urinary tract) demonstrated that SMT-738 significantly reduced the Bacterial burden compared to baseline and vehicle control. SMT-738 represents a promising novel drug candidate being developed to address clinically challenging serious life-threatening infections caused by highly resistant Enterobacteriaceae including CRE.

Keywords

SMT-738; bacterial lipoprotein transport; carbapenem-resistant Enterobacteriaceae.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157536
    98.47%, Enterobacteriaceae Inhibitor