Repurposing clinically approved cephalosporins for tuberculosis therapy

Area of Science:

• Microbiology
• Pharmacology
• Medicinal Chemistry

Background:

• Tuberculosis (TB) remains a global health challenge, necessitating novel therapeutic strategies.
• Modern cephalosporins are primarily developed for broad-spectrum antibacterial activity, not specifically for TB.
• Existing TB treatments face challenges with drug resistance and treatment duration.

Purpose of the Study:

• To investigate the potential of first-generation cephalosporins as anti-tuberculosis agents.
• To identify structure-activity relationships (SAR) for cephalosporin activity against Mycobacterium tuberculosis.
• To evaluate synergistic interactions between cephalosporins and existing or novel TB drugs.

Main Methods:

• Structure-activity relationship (SAR) studies were conducted to identify key chemical features for anti-mycobacterial activity.
• In vitro testing of various cephalosporins alone and in combination with anti-TB drugs, including rifampicin, ethambutol, bedaquiline, and delamanid.
• Assessment of drug synergy under both extracellular and intracellular mycobacterial growth conditions.
• Investigation of potential mechanisms of synergy, such as drug accumulation.

Main Results:

• First-generation cephalosporins demonstrated clinically relevant inhibitory concentrations against Mycobacterium tuberculosis.
• Significant synergistic activity was observed between cephalosporins and rifampicin (4- to 64-fold increase in activity), and ethambutol.
• Synergy was maintained under intracellular growth conditions.
• Clavulanate enhanced cephalosporin activity and restored rifampicin efficacy against resistant strains.
• Cephalosporins showed synergy with newer drugs like bedaquiline and delamanid.

Conclusions:

• First-generation cephalosporins possess anti-mycobacterial activity and can be synergistic with established and novel TB therapies.
• Their oral bioavailability and favorable safety profiles make them attractive candidates for repurposing in combination TB regimens.
• Further in vivo studies are warranted to validate the therapeutic potential of these cephalosporin-based combinations for tuberculosis treatment.