Year: 2026
Type: preprint
Abstract: ABSTRACT The emergence of drug-resistant strains of Mycobacterium tuberculosis makes anti-tubercular drug development a critical priority. Griselimycin is a cyclic peptide that targets the essential DNA sliding clamp of M. tuberculosis . While griselimycin is a promising antimycobacterial compound, its poorly understood structure-activity relationship has stalled derivatization. To investigate the contribution of each amino acid towards its activity, we assessed the antibiotic activity of an alanine scan library in M. tuberculosis . Incorporation of an N -terminal fluorophore enabled visualization of griselimycin accumulation inside of mycobacteria-infected macrophage cells. Derivatives containing altered cyclization chemistries, unnatural amino acids, expanded proline side chains, and alkyne handles were assessed, with a final design combining the most potent edits showing increased antibiotic activity. These findings present the comprehensive structure-activity investigation of griselimycin and can be used to rationally design future analogues. TABLE OF CONTENTS GRAPHIC
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7140041098