Targeting Gene Transcription Thwarts Antibiotic Resistance

Innovative strategies are needed to curb the global health challenge of antibiotic resistance. The World Health Organization predicts that antibiotic resistance could lead to 10 million deaths annually by 2050. Pharmaceutical experience has shown that modest alterations of commonly-used broad-spectrum antibiotics readily elicit resistant strains. Thus, continued simple iterative improvements on current antibiotics are not sustainable. In this brief Review, we discuss traditional strategies of targeting single sites with the goal of a broad-spectrum antibiotic. In comparison, we suggest a a novel strategy that targets multiple sites in single or multidrug-resistant Gram-positive bacterial pathogens. The task is to exploit the mechanisms by which pathogenic bacteria require genes for transcriptional regulation. Transcription regulatory factors can be manipulated and their functions thwarted to disrupt bacterial viability. Some transcription factors regulate one or more steps in metabolic pathways. Transcription factors are not always proteins, some are small molecule metabolites triggering genetic function through riboswitches and others are RNAs. We describe novel agents discovered with computer simulated docking to an unusual transcription regulatory site in nascent mRNA. These compounds exhibit innovative chemistries and modes of action that inhibit bacterial growth by binding to and blocking critical Gram-positive mRNA functions. Our studies of the tRNA-dependent transcription regulation of amino acid metabolism illustrate the possibilities of novel strategies to inhibit antibiotic-resistant growth and thwart emergence of novel resistant strains.