Kumar K C Ananth, Nair Adwaita, Sharma Shreya, Singh Deepika, Yadav Shivam, Bhimsaria Devesh, Gupta Sebanti, Hazra Saugata
Division of Data Analytics, Bioinformatics and Structural Biology, Yenepoya Research Centre, Yenepoya University, Mangalore, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, India.
J Antibiot (Tokyo). 2025 Aug 25. doi: 10.1038/s41429-025-00862-3.
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.
抗菌药物耐药性（AMR）的不断升级给全球公共卫生投下了沉重的阴影，使曾经易于控制的感染越来越难以治疗。尽管针对耐多药（MDR）和广泛耐药（XDR）结核分枝杆菌（TB）的联合化疗取得了进展，但这种病原体仍然是一个 formidable foe。TB现在是全球第二大传染病死亡原因，仅次于COVID-19。它是AMR相关死亡的主要驱动因素，尤其是在合并感染HIV的个体中。一个重大挑战在于TB对β-内酰胺类抗生素的耐药性，β-内酰胺类抗生素是使用最广泛的一类抗生素，占全球抗生素消费量的约65%。这种耐药性是由该细菌产生的β-内酰胺酶（BlaC）驱动的，它通过水解β-内酰胺环来中和抗生素。尽管BlaC对舒巴坦、他唑巴坦和克拉维酸等β-内酰胺酶抑制剂（MBIs）仍然敏感，但二级催化位点的耐药突变构成了新出现的威胁，可能会削弱这些抑制剂的作用。为了应对这一不断演变的挑战，一项全面的研究探讨了BlaC在AMR中的作用。该研究涵盖六个阶段，从基因和蛋白质序列分析到动态蛋白质建模和突变图谱探索。采用同源建模为所有40种BlaC变体生成结构，并通过拉氏图评估稳定性。通过自动对接和模拟研究，研究了六种β-内酰胺类药物和MBIs与药物-蛋白质的相互作用。这些见解为深入了解TB中BlaC介导的耐药性提供了依据，并为未来开发应对这一全球卫生危机的药物奠定了有希望的基础。
