Repurposing non-antimicrobial drugs to treat multi-drug resistant bacterial and fungal infections

<p>Bacterial and fungal resistance to conventional antimicrobials is a burgeoning global health epidemic that necessitates urgent action. Even more alarming, the development of new antimicrobials to treat these multidrug-resistant pathogens has not kept pace with the rapid emergence of resistance to current antimicrobials. Antimicrobial drug development through the traditional <em>de novo</em> process is a risky venture given the significant financial and time investment required by researchers and limited success rate of translating these compounds to the clinical setting. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). The main aim of this research endeavor was to screen and validate approved drug libraries and small molecules for their antimicrobial activity against multidrug-resistant bacterial and fungal pathogens, including<em>Staphylococcus aureus</em> and <em>Candida albicans</em>.</p> <p>The present study identified four approved drugs (auranofin, ebselen, simvastatin and celecoxib) that exhibited potent antimicrobial activity against multidrug-resistant bacterial and fungal pathogens. Notably, auranofin, an FDA-approved anti-rheumatic drug possessed excellent antibacterial activity against <em>S. aureus</em> and was found to exert its effect by inhibiting multiple biosynthetic pathways including DNA, protein and cell wall synthesis. Furthermore, auranofin was found to be efficacious in a mouse model of <em>S. aureus</em> systemic infection, as it significantly reduced the bacterial load in murine organs, including the spleen and liver. Ebselen, an organoselenium compound known to be clinically safe, exhibited potent anti-staphylococcal activity by inhibiting bacterial protein synthesis. Other approved drugs including simvastatin (anti-hyperlipedmic drug) and celecoxib (non-steroidal anti-inflammatory drug) also possessed anti-staphylococcal activity against various clinical isolates of <em>S. aureus</em>. Our study also revealed that three drugs (auranofin, ebselen and simvastatin) markedly reduced the production of major staphylococcal toxins including Panton-Valentine leucocidin (PVL) and α-hemolysin (Hla), thereby improving the treatment outcome against toxin-producing bacterial pathogens. Furthermore, all these drugs effectively reduced both the bacterial load and inflammatory cytokines in a mouse model of <em>S. aureus</em> skin infection.</p> <p>In addition to their antibacterial activity, auranofin and ebselen were found to possess potent antifungal activity against two major pathogens, <em>Candida</em> and <em>Cryptococcus</em>; they exerted their antifungal effect through inhibition of mitochondrial proteins (auranofin) and glutathione synthesis (ebselen) respectively. Additionally, these two drugs proved superior to control antifungals, as they reduced the fungal load in a <em>Caenorhabditis elegans</em> animal model. Taken altogether, the potent <em>in vitro </em>and <em>in vivo</em> antimicrobial activity (against bacterial and (or) fungal pathogens) of auranofin, ebselen, simvastatin and celecoxib indicates these four drugs have considerable promise to be successfully repurposed for use as antimicrobial agents.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Year

2016

Author dc:creator

• Thangamani, Shankar

Contributors dc:contributor

• Mohamed Seleem
• Kenitra Hammac
• Cynthia Stauffacher
• Suresh Mittal

• Biological sciences
• Health and environmental sciences
• Antimicrobial resistance
• Approved drugs
• Bacteria
• Drug discovery
• Fungi
• Repurposing
• Immunology and Infectious Disease
• Microbiology

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/1015

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-2230