Development of 2nd generation aminomethyl spectinomycins that overcome native efflux in Mycobacterium abscessus.

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.

Solvent Effects and Mechanistic Studies for Re2O7-Catalyzed Allylative Annulation Reactions.

The sequence of allylic alcohol transposition, carbonyl group trapping, oxocarbenium ion formation, and nucleophilic addition results in the formation of a ring while serving as a fragment-coupling and stereocenter-generating reaction. Successful applications of these processes require a balancing of the kinetics of numerous productive and unproductive steps. This work describes the manner in which solvent changes can be used to expand the scope and change the stereochemical outcomes of these processes. Mechanistic studies provide greater insight into the nuances of the transformations and the reactive species that are generated.

Condensation reactions of guanidines with bis-electrophiles: Formation of highly nitrogenous heterocycles.

2-Amino-1,4-dihydropyrimidines were reacted with bis-electrophiles to produce novel fused bi-pyrimidine, pyrimido-aminotriazine, and pyrimido-sulfonamide scaffolds. In addition, a quinazoline library was constructed using a guanidine Atwal-Biginelli reaction with 1-(quinazolin-2-yl)guanidines. The product heterocycles have novel constitutions with high nitrogen atom counts and represent valuable additions to screening libraries for the discovery of new modulators of biological targets.

Targeting Helicobacter pylori for antibacterial drug discovery with novel therapeutics.

Helicobacter pylori is an important human pathogen with increasing antimicrobial resistance to standard-of-care antibiotics. Treatment generally includes a combination of classical broad-spectrum antibiotics and a proton-pump inhibitor, which often leads to perturbation of the gut microbiome and the potential for the development of antibiotic resistance. In this review, we examine reports, primarily from the past decade, on the discovery of new anti-H. pylori therapeutics, including approaches to develop narrow-spectrum and mechanistically unique antibiotics to treat these infections in their gastric niche. Compound series that target urease, respiratory complex I, and menaquinone biosynthesis are discussed in this context, along with bivalent antibiotic approaches that suppress resistance development. With increases in the understanding of the unique physiology of H. pylori and technological advances in the field of antibacterial drug discovery, there is a clear promise that novel therapeutics can be developed to effectively treat H. pylori infections.