Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19 F ligand-observed NMR experiments.
It is critical that novel classes of antituberculosis
drugs are
developed to combat the increasing burden of infections by multidrug-resistant
strains. To identify such a novel class of antibiotics, a chemical
library of unique 3-D bioinspired molecules was explored revealing
a promising, mycobacterium specific Tricyclic SpiroLactam (TriSLa)
hit. Chemical optimization of the TriSLa scaffold delivered potent
analogues with nanomolar activity against replicating and nonreplicating Mycobacterium tuberculosis. Characterization of isolated
TriSLa-resistant mutants, and biochemical studies, found TriSLas to
act as allosteric inhibitors of type II NADH dehydrogenases (Ndh-2
of the electron transport chain), resulting in an increase in bacterial
NADH/NAD+ ratios and decreased ATP levels. TriSLas are
chemically distinct from other inhibitors of Ndh-2 but share a dependence
for fatty acids for activity. Finally, in vivo proof-of-concept studies
showed TriSLas to protect zebrafish larvae from Mycobacterium
marinum infection, suggesting a vulnerability of Ndh-2
inhibition in mycobacterial infections.
The restrictions posed by the COVID-19 pandemic obliged the French Society for Medicinal Chemistry (Société de chimie thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) to organize their joint autumn symposium (entitled “On the hunt for next-generation antimicrobial agents”) online on 9–10 December 2021. The meeting attracted more than 200 researchers from France and abroad with interests in drug discovery, antimicrobial resistance, medicinal chemistry, and related disciplines. This review summarizes the 13 invited keynote lectures. The symposium generated high-level scientific dialogue on the most recent advances in combating antimicrobial resistance. The University of Lille, the Institut Pasteur de Lille, the journal Pharmaceuticals, Oxeltis, and INCATE, sponsored the event.
The concept of privileged structure has been used as a fruitful approach for the discovery of novel biologically active molecules. A privileged structure is defined as a semi-rigid scaffold able to display substituents in multiple spatial directions and capable of providing potent and selective ligands for different biological targets through the modification of those substituents. On average, these backbones tend to exhibit improved drug-like properties and therefore represent attractive starting points for hit-to-lead optimization programs. This article promotes the rapid, reliable, and efficient synthesis of novel, highly 3-dimensional, and easily functionalized bio-inspired tricyclic spirolactams, as well as an analysis of their drug-like properties.
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