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

E B M Breidenstein1, N Khan1, T Duffy1

  • 1Summit Therapeutics, The Works, Unity Campus , Cambridge, United Kingdom.

Antimicrobial Agents and Chemotherapy
|December 12, 2023
PubMed

Insights

A new drug, SMT-738, shows potent activity against carbapenem-resistant Enterobacteriaceae (CRE). This novel agent targets essential bacterial mechanisms, offering a promising solution for difficult-to-treat infections.

Area of Science:

  • Microbiology and Infectious Diseases
  • Pharmacology and Drug Development

Background:

  • Carbapenem-resistant Enterobacteriaceae (CRE) pose an urgent global health threat, necessitating novel therapeutic strategies.
  • Existing treatments are limited, driving the need for new antimicrobial agents effective against multidrug-resistant pathogens.

Purpose of the Study:

  • To characterize the microbiological, mechanistic, safety, and pharmacokinetic/pharmacodynamic (PK/PD) profile of SMT-738, a novel small molecule.
  • To evaluate SMT-738's efficacy in preclinical models of Gram-negative bacterial infections.

Main Methods:

  • Microbiological profiling, including minimum inhibitory concentration (MIC) determination against key Enterobacterales.
  • Mechanism of action studies identifying target mutations in the lipoprotein transport complex (LolCDE).
  • In vitro toxicology, pharmacokinetic (PK) studies in animal models, and in vivo efficacy testing in murine infection models (bloodstream, pneumonia, urinary tract).

Main Results:

  • SMT-738 demonstrated potent in vitro activity against multidrug-resistant Escherichia coli and Klebsiella pneumoniae (MIC90 of 1-2 µg/mL).
  • The compound exhibits rapid bactericidal activity, low propensity for resistance development, and targets the essential LolCDE complex.
  • In vivo studies showed significant bacterial burden reduction in bloodstream, pneumonia, and urinary tract infection models, with favorable PK and safety profiles.

Conclusions:

  • SMT-738 is a promising novel drug candidate with a unique mechanism of action against challenging Gram-negative pathogens.
  • Its favorable in vitro and in vivo profiles support further development for treating serious infections caused by carbapenem-resistant Enterobacteriaceae.
Keywords:
SMT-738bacterial lipoprotein transportcarbapenem-resistant Enterobacteriaceae

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