A natural product from Streptomyces targets PhoP and exerts anti-virulence action against Salmonella enterica

BRUNA, ROBERTO; CASAL, ALEJO; BERCOVICH, BÁRBARA; GRAMAJO, HUGO; EDUARDO RODRIGUEZ; GARCIA VESCOVI, ELEONORA

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY

OXFORD UNIV PRESS

Lugar: Oxford; Año: 2022

0305-7453

Background: The over-prescription and misuse of classical antimicrobial compounds to treat gastrointestinal or systemic salmonellosis have been accelerating the surge of antibiotic-recalcitrant bacterial populations, posing a major public health challenge. Therefore, alternative therapeutic approaches to treat Salmonella-borne infections are urgently required. Objectives: To identify and characterize actinobacterial secreted compounds with inhibitory properties against Salmonella enterica PhoP/PhoQ signal transduction system, crucial for virulence regulation. Methods: The methodology was based on a combination of the measurement of PhoP/PhoQ-dependent and -independent reporter genes activity and bio-guided assays to screen for bioactive inhibitory metabolites present in culture supernatants obtained from a collection of actinobacterial isolates. Analogues of azomycin were used to analyze the functional groups required for the detected bioactivity and Salmonella mutants and complemented strains helped to dissect azomycin mechanism of action. The tetrazolium dye colorimetric assay was used to investigate azomycin potential cytotoxicity on cultured macrophages. Salmonella intramacrophage replication capacity upon azomycin treatment was assessed using the gentamicin protection assay. Results: Sublethal concentrations of azomycin, a nitroheterocyclic compound naturally produced by Streptomyces eurocidicus, repressed the Salmonella PhoP/PhoQ system activity by targeting PhoP and inhibiting its transcriptional activity, in a PhoQ- and aspartate phosphorylation -independent manner. Sublethal, non-cytotoxic concentrations of azomycin prevented Salmonella intramacrophage replication.