β-Lactam Antibiotic Strategies Against Drug-Resistant Tuberculosis

The current tuberculosis pandemic is driven by multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains that evade first-line agents. Although β-lactam antibiotics have historically been excluded from standard TB therapy due to innate mycobacterial β-lactamases and unique cell envelope barriers, recent insights have revived their potential. Strategies now encompass combination regimens with β-lactamase inhibitors to neutralise hydrolytic enzymes, co-administration with cell-wall-disrupting partner drugs to enhance penetration, and structure-guided design of inhibitors that target both classical penicillin-binding proteins and non-classical l,d-transpeptidases responsible for 3→3 cross-links in peptidoglycan. High-resolution structural studies and novel screening platforms are informing the rational modification of existing β-lactam scaffolds, while CRISPR-based genetic tools are identifying peptidoglycan modification pathways that confer resistance. Together, these approaches are reshaping the clinical and chemical toolkit for tackling drug-resistant Mycobacterium tuberculosis on a global scale, offering promising avenues for more efficacious regimens with well-characterised safety profiles.

Research from Nature Portfolio

Recent studies have resolved the crystal structure of a major non-classical l,d-transpeptidase in complex with its natural peptidoglycan substrate, revealing the precise thioester intermediate that forms between the catalytic cysteine and the tetrapeptide monomer. This insight clarifies substrate entry pathways and active-site conformational changes, providing a template for the rational design of novel inhibitors that exploit substrate-binding interactions. In parallel, structure–activity analyses of first-generation cephalosporins have uncovered key chemical motifs that confer anti-tubercular potency and synergy with standard drugs such as rifampicin and ethambutol. These cephalosporins, when paired with β-lactamase inhibitors, demonstrate both in vitro and intracellular activity at clinically relevant concentrations, underscoring the feasibility of repurposing orally available β-lactams in combination regimens against resistant strains.

β-Lactam Antibiotic Strategies Against Drug-Resistant Tuberculosis publication trend

The graph below shows the total number of articles in β-lactam antibiotic strategies against drug-resistant tuberculosis across all publications each year (not limited to Nature Index journals).

Technical terms

β-Lactam antibiotic: A class of antimicrobial agents defined by a four-membered β-lactam ring that acylates and inhibits bacterial transpeptidases.

Peptidoglycan: A structural polymer of alternating sugar and amino acid chains that provides rigidity to the bacterial cell wall.

l,d-Transpeptidase: A non-classical enzyme that forms 3→3 peptide cross-links in peptidoglycan and can bypass classical d,d-transpeptidases.

Penicillin-Binding Protein: A family of classical d,d-transpeptidases that catalyse 4→3 cross-linking in peptidoglycan synthesis.

Carbapenem: A subclass of β-lactam antibiotics characterised by broad-spectrum activity and stability against many β-lactamases.

β-Lactamase inhibitor: A compound that binds to and neutralises β-lactamase enzymes, preserving the activity of β-lactam antibiotics.

References

1. High-throughput screen with the l,d -transpeptidase Ldt Mt2 of Mycobacterium tuberculosis reveals novel classes of covalently reacting inhibitors. Chemical Science (2023).
2. Biochemical and crystallographic studies of l,d-transpeptidase 2 from Mycobacterium tuberculosis with its natural monomer substrate. Communications Biology (2024).
3. CRISPRi-mediated characterization of novel anti-tuberculosis targets: Mycobacterial peptidoglycan modifications promote beta-lactam resistance and intracellular survival. Frontiers in Cellular and Infection Microbiology (2023).
4. Ethambutol and meropenem/clavulanate synergy promotes enhanced extracellular and intracellular killing of Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy (2024).
5. Repurposing clinically approved cephalosporins for tuberculosis therapy. Scientific Reports (2016).
6. Structural Insights into the Penicillin-Binding Protein 4 (DacB) from Mycobacterium tuberculosis. International Journal of Molecular Sciences (2024).