Fragment-like pyrazole-tetrazoles provide a scaffold for antibiofilm drug discovery

ABSTRACT: Antimicrobial drug discovery is at a standstill, with many frontline antimicrobial drug classes identified in the previous century. Many human pathogens are now resistant to many of these classes, straining the healthcare system and putting lives at risk. ESKAPE pathogens are among the most commonly resistant, many of which are multidrug-resistant. Biofilms are just one of the many mechanisms by which ESKAPE pathogens circumvent antimicrobial treatment, leading to persistent infection and death. To counter the threat posed by ESKAPE pathogens in biofilms, we evaluated fragment-like pyrazole-tetrazole scaffolds for antibiofilm activity using standard in vitro assays, including crystal violet staining, confocal microscopy of biofilm structure, and RNA sequencing to identify potential targets for this scaffold. We found that the pyrazole-tetrazole scaffold compound 5 exhibits robust antibiofilm activity against Staphylococcus aureus, with marginal activity against Enterococcus faecium, as shown by crystal violet experiments. Compound 5 not only limited biofilm formation but also killed mature biofilms by altering the structure of biofilms observed through confocal microscopy. RNA sequencing revealed reprogramming of both forming and mature biofilms upon treatment with compound 5, with gene expression more closely reverting to planktonic growth. These results demonstrate a fragment-like scaffold with robust anti-biofilm-specific activity for future drug development.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE348130 | GEO | 2026/10/01

REPOSITORIES: GEO