Research Projects

Antimicrobial resistance (AMR) in bacteria is a critical public health concern in India and globally. AMR is often described as a silent pandemic, with the potential to cause 28 million deaths by 2050 and severely impact the global economy. Additionally, multidrug-resistant tuberculosis (MDR-TB) is a significant threat to public health, with India reporting 22% of all cases worldwide, the highest prevalence of MDR-TB globally. This growing challenge of AMR underscores the need for the sustained discovery and development of durable novel antimicrobials. Macrolide antibiotics (e.g., erythromycin, azithromycin, tylosin) are effective against a broad range of bacterial infections. They primarily target Gram-positive bacteria and select Gram-negative organisms such as Neisseria gonorrhoeae. Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. Resistance arises via antibiotic inactivation, target modification (erm gene-mediated A2058 methylation), and efflux pumps (mef gene). Mycobacteria possess the erm gene, making them intrinsically resistant, while Gram-negative bacteria resist macrolides due to their outer membrane. Semi-synthetic macrolides like telithromycin, solithromycin, and nafithromycin show some success against mef-mediated resistance, but no macrolide analogue effectively overcomes both erm- and mef-mediated resistance, or the intrinsic resistance of Gram-negatives and mycobacteria. We propose a semi-synthetic platform based on tylosin, a 16-membered macrolide currently restricted to veterinary use due to nephrotoxicity. Its aldehyde group, while crucial for activity, also functions as a toxicophore, contributing to toxicity. While it facilitates covalent interactions with RNA nucleobases (A2062), its instability under acidic and alkaline conditions, along with its tendency to react with nucleophiles in physiological environments, leads to cytotoxic effects. To address this, we aim to replace the aldehyde with electron-deficient hydrophobic aromatic or globular moieties that promote alternative, non-covalent interactions. These modifications are expected to reduce desolvation energy, enhance ribosome binding through π-π stacking (e.g., with A2062), and stabilize the drug-target complex. Additionally, we propose removing one or two non-essential sugar units from tylosin to enhance lipophilicity and improve membrane penetration, particularly in Gram-negative bacteria and mycobacteria. Together, these strategies aim to broaden tylosin’s spectrum, overcoming intrinsic resistance in Gram-negative bacteria and mycobacteria, while retaining potency against both sensitive and resistant Gram-positive strains. The proposed tylosin derivatives will be synthesized, with the final step involving reductive amination, followed by sequential cleavage of non-essential sugar units under mild acidic conditions to generate a library of analogues. All compounds will be thoroughly characterized and purified to 95% purity before evaluating their antibacterial activities according to Clinical Laboratory Standard Institute (CLSI) guidelines. Molecular docking and mechanistic studies will be conducted to elucidate structure–activity relationships. Lead candidates will then be assessed in murine infection models. Preliminary findings support our hypothesis that replacing the aldehyde toxicophore with hydrophobic aromatic moieties, along with increased hydrophobicity via sugar removal, can effectively overcome both intrinsic and acquired macrolide resistance. Our proposed semi-synthetic platform aims to eliminate tylosin’s toxicity, making it suitable for both human and veterinary use, while overcoming macrolide resistance, including mef-, erm-, and intrinsic Gram-negative resistance. This strategy repurposes a veterinary antibiotic into a broad-spectrum agent, aligning with the WHO’s “One Health” initiative that links human, animal, and environmental health, and offers significant clinical potential.