Exploring β-lactam interactions with DacB1: unraveling optimal therapies for combating drug-resistant

Tuberculosis (TB) continues to pose a global public health threat, exacerbated by rising drug-resistant strains of IMPORTANCE: TB remains a significant public health threat, particularly due to the rising prevalence of drug-resistant Mtb strains. Current treatment options for drug-resistant TB are costly, toxic, and often ineffective, necessitating the exploration of alternative therapeutic strategies. This study is of critical importance as it investigates the potential of β-lactam antibiotics (BLs), a class historically considered ineffective against Mtb, for repurposing in TB treatment. By targeting DacB1, a key enzyme in Mtb peptidoglycan biosynthesis, this research provides new insights into the mechanism of β-lactam interactions and their potential to disrupt cell wall synthesis. The findings demonstrate that dual β-lactam therapy and β-lactam/β-lactamase inhibitor combinations enhance antibiotic efficacy, suggesting a promising avenue for combating drug-resistant TB. Furthermore, structural and molecular analyses confirm that carbapenems, particularly imipenem, meropenem, and tebipenem, effectively bind to DacB1, paving the way for optimized treatment strategies. Given the challenges in developing new TB drugs, repurposing β-lactams offers a cost-effective and readily implementable solution to address antimicrobial resistance. This study contributes valuable knowledge that could accelerate the development of novel TB therapies, improve treatment success rates, and ultimately reduce TB-related mortality worldwide.