Strategic design of a multi-tier database for class A β-lactamase BlaC variants of M. tuberculosis: advancing the fight against antibacterial resistance

The escalating rise of antimicrobial resistance (AMR) casts a grave shadow over global public health, making once manageable infections increasingly difficult to treat. Despite advancements in combination chemotherapy for multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (TB), this pathogen remains a formidable foe. TB is now the second leading cause of death worldwide from infectious diseases, only surpassed by COVID-19. It is the primary driver of AMR-related deaths, particularly among HIV co-infected individuals. A significant challenge lies in TB's resistance to β-lactam antibiotics, the most widely used class, comprising about 65% of global antibiotic consumption. This resistance is driven by the bacterium's β-lactamase enzyme (BlaC) production, which neutralizes the antibiotic by hydrolyzing the β-lactam ring. Although BlaC remains susceptible to β-lactamase inhibitors (MBIs) like sulbactam, tazobactam, and clavulanate, resistance mutations in secondary catalytic sites pose an emerging threat, potentially undermining these inhibitors. To combat this evolving challenge, a comprehensive study explored BlaC's role in AMR. The research spanned six phases, from gene and protein sequence analysis to dynamic protein modelling and mutational landscape exploration. Homology modelling was employed to generate structures for all 40 BlaC variants, with stability assessed through Ramachandran plots. Drug-protein interactions with six β-lactam agents and MBIs were investigated via automated docking and simulation studies. These insights provide a deeper understanding of BlaC-mediated resistance in TB and offer a promising foundation for future drug development to address this global health crisis.