Inhibitors of pathogen intercellular signals as selective anti-infective compounds.
Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens.
Lesic
Biliana
B
Department of Surgery, Microbiology and Molecular Genetics, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
Lépine
François
F
Déziel
Eric
E
Zhang
Jiangwen
J
Zhang
Qunhao
Q
Padfield
Katie
K
Castonguay
Marie-Hélène
MH
Milot
Sylvain
S
Stachel
Scott
S
Tzika
A Aria
AA
Tompkins
Ronald G
RG
Rahme
Laurence G
LG
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000502:physiology; D015964:Gene Expression Regulation, Bacterial; D051379:Mice; D008815:Mice, Inbred Strains; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000502:physiology*; D011804:Quinolines / Q000378:metabolism; D053038:Quorum Sensing / Q000187:drug effects* / Q000502:physiology*; D014774:Virulence; D014776:Virus Cultivation; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000378:metabolism
D000900:Anti-Bacterial Agents; D011804:Quinolines; D062367:ortho-Aminobenzoates; C031385:anthranilic acid