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

BRUNA, R.; CASAL, A. ; BERCOVICH, B; GRAMAJO, H.; RODRIGUEZ, E. ; GARCIA VESCOVI, E

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY

OXFORD UNIV PRESS

Lugar: Oxford; Año: 2022

0305-7453

AbstractBackground: The over-prescription and misuse ofclassical antimicrobial compounds to treat gastrointestinal or systemicsalmonellosis have been accelerating the surge of antibiotic-recalcitrantbacterial populations, posing a major public health challenge. Therefore,alternative therapeutic approaches to treat Salmonella-borne infectionsare urgently required. Objectives: To identify and characterizeactinobacterial secreted compounds with inhibitory properties against Salmonellaenterica PhoP/PhoQ signal transduction system, crucial for virulenceregulation. Methods: The methodology was based on a combinationof the measurement of PhoP/PhoQ-dependent and -independent reporter genesactivity and bio-guided assays to screen for bioactive inhibitory metabolites presentin culture supernatants obtained from a collection of actinobacterial isolates.Analogues of azomycin were used to analyze the functional groups required forthe detected bioactivity and Salmonella mutants and complemented strainshelped to dissect azomycin mechanism of action. The tetrazolium dyecolorimetric assay was used to investigate azomycin potential cytotoxicity oncultured macrophages. Salmonella intramacrophage replication capacity uponazomycin treatment was assessed using the gentamicin protection assay. Results: Sublethal concentrations of azomycin, anitroheterocyclic compound naturally produced by Streptomyces eurocidicus,repressed the Salmonella PhoP/PhoQ system activity by targeting PhoP andinhibiting its transcriptional activity, in a PhoQ- and aspartatephosphorylation -independent manner. Sublethal, non-cytotoxic concentrations ofazomycin prevented Salmonella intramacrophage replication.