ACS Infect Dis. 2021 Dec 10;7(12):3314-3335. doi: 10.1021/acsinfecdis.1c00466. Epub 2021 Nov 12.

Structure-Activity Studies with Bis-Amidines That Potentiate Gram-Positive Specific Antibiotics against Gram-Negative Pathogens.

ACS infectious diseases

Charlotte M J Wesseling, Cornelis J Slingerland, Shanice Veraar, Samantha Lok, Nathaniel I Martin

PMID: 34766746 DOI: 10.1021/acsinfecdis.1c00466

Abstract

Pentamidine, an FDA-approved antiparasitic drug, was recently identified as an outer membrane disrupting synergist that potentiates erythromycin, rifampicin, and novobiocin against Gram-negative bacteria. The same study also described a preliminary structure-activity relationship using commercially available pentamidine analogues. We here report the design, synthesis, and evaluation of a broader panel of bis-amidines inspired by pentamidine. The present study both validates the previously observed synergistic activity reported for pentamidine, while further assessing the capacity for structurally similar bis-amidines to also potentiate Gram-positive specific antibiotics against Gram-negative pathogens. Among the bis-amidines prepared, a number of them were found to exhibit synergistic activity greater than pentamidine. These synergists were shown to effectively potentiate the activity of Gram-positive specific antibiotics against multiple Gram-negative pathogens such as

Keywords: antibiotic synergy; bis-amidines; checkerboard assays; outer membrane disruption

Publication Types

• Journal Article