Infections caused by Gram-positive pathogens, including Clostridium difficile, are a leading cause of mortality. Three species?methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae and vancomycin-resistant enterococcus (VRE)?are responsible annually for at least 84% of deaths due to antibiotic- resistant infections. C. difficile is the most common and costly healthcare-associated infection with an estimated 29,000 deaths annually. Only one new antibiotic, fidaxomicin, has been approved in the last 30 years for treatment of C. difficile infection and recurrence rates are still high for infections involving hypervirulent strains. There is a desperate need for new drugs with improved efficacy. Unlike the costly and time-consuming process of de novo drug discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation. Studies proposed in this application focus on repurposing one non-antimicrobial approved drug, auranofin, and one clinical molecule, ebselen. These two agents possess potent antibacterial activity, in a low nano molar concentration achievable at a clinical range, against multidrug-resistant pathogens, including MRSA, VRE, and C. difficile. We have demonstrated (in vitro and in vivo) that both drugs are superior to drugs of choice and are capable of 1) killing intracellular and persistent MRSA, 2) disrupting adherent staphylococcal biofilms, 3) suppressing key virulence factors including toxin production, 4) reducing excessive host-inflammatory responses associated with these toxins, 5) significantly reducing both the bacterial load and levels of the pro- inflammatory cytokines in MRSA skin lesions, and 6) enhancing wound healing. Both drugs have additional advantageous qualities against C. difficile including; a) potent activity achievable in a clinical range, b) inhibiting toxin production, c) neutralizing C. difficile toxins by inhibiting the cysteine protease domain, d) inhibiting spore formation, e) inhibiting IL-8 release and protecting cells from effect of toxins, f) preventing intestinal colonization of VRE, and were g) superior to drugs of choice in in vitro testing. The fact that auranofin has been granted orphan-drug status from the FDA for treatment of intestinal amebiasis, and is currently in a Phase II clinical trial for treatment of intestinal giardiasis, further validates our approach. Our overall goal in this application is to further validate auranofin and ebselen as potential treatments for superficial, systemic and intestinal infections caused by multidrug-resistant bacterial pathogensand C. difficile. Our findings in MRSA, VRE and C. difficile will be broadly relevant to other pathogens and may offer a safe, effective, and quick supplement to current approaches for treating bacterial infections.

Public Health Relevance

Drug-resistance bacterial infections have become a serious threat to the global public health due to the dearth of effective antimicrobials. There is no doubt that there is a critical unmet need for a novel antibacterial agent to treat these infections. The proposed research is expected to have a significant positive impact on human health by validating non-antimicrobial FDA approved drugs as antimicrobial agents, which may lead to the development of a new class of antimicrobial drug that can be used to treat infections caused by highly resistant pathogens.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Purdue University
Veterinary Sciences
Schools of Veterinary Medicine
West Lafayette
United States
Zip Code
Kotb, Ahmed; Abutaleb, Nader S; Seleem, Mohamed A et al. (2018) Phenylthiazoles with tert-Butyl side chain: Metabolically stable with anti-biofilm activity. Eur J Med Chem 151:110-120
Mohammad, Haroon; AbdelKhalek, Ahmed; Abutaleb, Nader S et al. (2018) Repurposing niclosamide for intestinal decolonization of vancomycin-resistant enterococci. Int J Antimicrob Agents 51:897-904
AbdelKhalek, Ahmed; Abutaleb, Nader S; Mohammad, Haroon et al. (2018) Repurposing ebselen for decolonization of vancomycin-resistant enterococci (VRE). PLoS One 13:e0199710
Hagras, Mohamed; Hegazy, Youssef A; Elkabbany, Amr H et al. (2018) Biphenylthiazole antibiotics with an oxadiazole linker: An approach to improve physicochemical properties and oral bioavailability. Eur J Med Chem 143:1448-1456
AbdelKhalek, Ahmed; Abutaleb, Nader S; Elmagarmid, Khalifa A et al. (2018) Repurposing auranofin as an intestinal decolonizing agent for vancomycin-resistant enterococci. Sci Rep 8:8353
AbdelKhalek, Ahmed; Abutaleb, Nader S; Mohammad, Haroon et al. (2018) Antibacterial and antivirulence activities of auranofin against Clostridium difficile. Int J Antimicrob Agents :
Eldesouky, Hassan E; Mayhoub, Abdelrahman; Hazbun, Tony R et al. (2018) Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs. Antimicrob Agents Chemother 62:
Mohammad, Haroon; Elghazawy, Nehal H; Eldesouky, Hassan E et al. (2018) Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis. ACS Infect Dis 4:403-414
Elsebaei, Mohamed M; Mohammad, Haroon; Abouf, Mohamed et al. (2018) Alkynyl-containing phenylthiazoles: Systemically active antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA). Eur J Med Chem 148:195-209
Eid, Islam; Elsebaei, Mohamed M; Mohammad, Haroon et al. (2017) Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis. Eur J Med Chem 139:665-673

Showing the most recent 10 out of 12 publications