Failing upwards: Genetics-based strategies to improve antibiotic discovery and efficacy in Mycobacterium tuberculosis

Abstract

Therapeutic advances in the 20th century significantly reduced tuberculosis (TB) mortality. Nonetheless, TB still poses a massive global health challenge with significant annual morbidity and mortality that has been amplified during the COVID-19 pandemic. Unlike most common bacterial infectious diseases, successful TB treatment requires months-long regimens, which complicates the ability to treat all cases quickly and effectively. Improving TB chemotherapy by reducing treatment duration and optimizing combinations of drugs is an important step to reducing relapse. In this review, we outline the limitations of current multidrug regimens against TB and have reviewed the genetic tools available to improve the identification of drug targets. The rational design of regimens that sterilize diverse phenotypic subpopulations will maximize bacterial killing while minimizing both treatment duration and infection relapse. Importantly, the TB field currently has all the necessary genetic and analytical tools to screen for and prioritize drug targets in vitro based on the vulnerability of essential and nonessential genes in the Mtb genome and to translate these findings in in vivo models. Combining genetic methods with chemical screens offers a formidable strategy to redefine the preclinical design of TB therapy by identifying powerful new targets altogether, as well as targets that lend new efficacy to existing drugs.

Perspectives on Usage of Functional Nanomaterials in Antimicrobial Therapy for Antibiotic-Resistant Bacterial Infections

“…In another work, AgNPs and zinc oxide nanoparticles encased in PLGA were employed to transport the antituberculosis rifampin into M. tuberculosis-infected alveolar macrophages. , The antibacterial effects were enhanced by the potential of silver nanoparticles and zinc oxide nanoparticles to engage with and weaken the integrity of bacterial membranes. Nanomaterial-based techniques to fight additional intracellular infections have also been explored.…”

Target Identification in Anti-Tuberculosis Drug Discovery

“…While historically effective, high-throughput screenings encounter several challenges in TB drug discovery. Despite the fact that they have general high hit rates, many compounds have undesirable physicochemical attributes, low selectivity, and mammalian cytotoxicity [ 17 , 21 ]. With the evolution of genomic tools, target-based screenings on validated drug targets, presumed to be indispensable for the survival of Mtb and pathogenicity, have gained some attention.…”

High‐throughput functional genomics: A (myco)bacterial perspective

“…Bacterial genomes typically comprise several hundreds to thousands of genes (Bentley & Parkhill, 2004 ), most of which are individually dispensable for growth and survival (Rancati et al, 2017 ). Essential genes are of special interest for establishing the minimal set of genes required to sustain life (Gil et al, 2004 ; Hogan & Cardona, 2022 ; Juhas et al, 2011 ; Lachance et al, 2019 ; Martínez‐Carranza et al, 2018 ) and because they encode putative targets of antibiotics in bacterial pathogens (Juhas et al, 2012 ; Tomasi & Rubin, 2022 ; Zhang et al, 2004 ). Screens using pooled and arrayed Tn mutant libraries have proven powerful in defining essential genes in diverse bacteria (Rancati et al, 2017 ).…”