4,5-Disubstituted 6‑Aryloxy-1,3-dihydrobenzo[<i>c</i>][1,2]oxaboroles Are Broad-Spectrum Serine β‑Lactamase Inhibitors

Bacterially expressed β-lactamases are rapidly eroding the clinical utility of the important β-lactam class of antibacterials, significantly impairing our ability to fight serious bacterial infections. This paper describes a study of oxaborole-derived β-lactamase inhibitors in which crystal structures and computational modeling aided in the rational design of analogues with improved spectrum of activity against class A, C, and D enzymes. Crystal structures of two of these inhibitors covalently bound to two different serine β-lactamases, class C Pseudomonas aeruginosa AmpC and class D OXA-10, are described herein. Improved physicochemical properties as well as increased activity against an array of β-lactamases resulted in substantial restoration of susceptibility to ceftazidime in Escherichia coli and Klebsiella pneumoniae

Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping

Fatty acid biosynthesis is essential to bacterial growth in Gram-negative pathogens. Several small molecules identified through a combination of high-throughput and fragment screening were cocrystallized with FabH (β-ketoacyl-acyl carrier protein synthase III) from Escherichia coli and Streptococcus pneumoniae. Structure-based drug design was used to merge several scaffolds to provide a new class of inhibitors. After optimization for Gram-negative enzyme inhibitory potency, several compounds demonstrated antimicrobial activity against an efflux-negative strain of Haemophilus influenzae. Mutants resistant to these compounds had mutations in the FabH gene near the catalytic triad, validating FabH as a target for antimicrobial drug discovery

Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure–activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg^–1. In vitro mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target

Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure–activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg^–1. In vitro mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target

Identification, Characterization, and Optimization of 2,8-Disubstituted-1,5-naphthyridines as Novel <i>Plasmodium falciparum</i> Phosphatidylinositol-4-kinase Inhibitors with in Vivo Efficacy in a Humanized Mouse Model of Malaria

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure–activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite <i>Plasmodium falciparum</i>. In the humanized <i>P. falciparum</i> mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg^–1. In vitro mode-of-action studies revealed <i>Plasmodium falciparum</i> phosphatidylinositol-4-kinase as the target

Pyrazolopyrimidines Establish MurC as a Vulnerable Target in <i>Pseudomonas aeruginosa</i> and <i>Escherichia coli</i>

The bacterial peptidoglycan biosynthesis pathway provides multiple targets for antibacterials, as proven by the clinical success of β-lactam and glycopeptide classes of antibiotics. The Mur ligases play an essential role in the biosynthesis of the peptidoglycan building block, <i>N</i>-acetyl-muramic acid-pentapeptide. MurC, the first of four Mur ligases, ligates l-alanine to UDP-<i>N</i>-acetylmuramic acid, initiating the synthesis of pentapeptide precursor. Therefore, inhibiting the MurC enzyme should result in bacterial cell death. Herein, we report a novel class of pyrazolopyrimidines with subnanomolar potency against both <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i> MurC enzymes, which demonstrates a concomitant bactericidal activity against efflux-deficient strains. Radio-labeled precursor incorporation showed these compounds selectively inhibited peptidoglycan biosynthesis, and genetic studies confirmed the target of pyrazolopyrimidines to be MurC. In the presence of permeability enhancers such as colistin, pyrazolopyrimidines exhibited low micromolar MIC against the wild-type bacteria, thereby, indicating permeability and efflux as major challenges for this chemical series. Our studies provide biochemical and genetic evidence to support the essentiality of MurC and serve to validate the attractiveness of target for antibacterial discovery