Abstract

Pseudomonas aeruginosa is a clinically important pathogen that causes a variety of infections, including urinary, respiratory, and other soft-tissue infections, particularly in hospitalized patients with immune defects, cystic fibrosis, or significant burns. Antimicrobial resistance is a substantial problem in P. aeruginosa treatment due to the inherent insensitivity of the pathogen to a wide variety of antimicrobial drugs and its rapid acquisition of additional resistance mechanisms. One strategy to circumvent this problem is the use of anti-virulent compounds to disrupt pathogenesis without directly compromising bacterial growth. One of the principle regulatory mechanisms for P. aeruginosa’s virulence is the iron-scavenging siderophore pyoverdine, as it governs in-host acquisition of iron, promotes expression of multiple virulence factors, and is directly toxic. Some combination of these activities renders pyoverdine indispensable for pathogenesis in mammalian models. Here we report identification of a panel of novel small molecules that disrupt pyoverdine function. These molecules directly act on pyoverdine, rather than affecting its biosynthesis. The compounds reduce the pathogenic effect of pyoverdine and improve the survival of Caenorhabditis elegans when challenged with P. aeruginosa by disrupting only this single virulence factor. Finally, these compounds can synergize with conventional antimicrobials, forming a more effective treatment. These compounds may help to identify, or be modified to become, viable drug leads in their own right. Finally, they also serve as useful tool compounds to probe pyoverdine activity.

Highlights

  • Despite advances in antimicrobial chemotherapy, multidrug resistant bacteria continue to cause life-threatening infections, especially in hospitals and with immunocompromised patients

  • We have previously demonstrated that some of the hits acted by interfering with bacterial iron metabolism (Kirienko et al, 2013) or by inhibiting the production of pyoverdine (Kirienko et al, 2016)

  • We observed that anti-pyoverdine compounds can quench the fluorescence of pyoverdine in cell-free filtrates, limit the expression of pyoverdine-dependent genes, and improve C. elegans survival after exposure to P. aeruginosa strain PA14

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Summary

Introduction

Despite advances in antimicrobial chemotherapy, multidrug resistant bacteria continue to cause life-threatening infections, especially in hospitals and with immunocompromised patients. P. aeruginosa expresses four major efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM) that effectively reduce intracellular drug concentrations, preventing the compounds from reaching intracellular doses required for effect (Lomovskaya et al, 2001). These pumps confer resistance to several classes of commonly used drugs, including β-lactams, fluoroquinolones, and aminoglycosides (Poole et al, 1993, 1996; Köhler et al, 1997; Aires et al, 1999). The development and approval of new antimicrobials (especially new classes of antimicrobials) is typically a slower process than the development of resistance by the pathogen which contributes to the increasing demand to at least supplement drug development efforts with novel treatment avenues for P. aeruginosa infections

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