Signature Research Projects
Drug Repurposing for Antimicrobial Resistance
Drug repurposing is gaining momentum due to the benefits of bypassing extensive preclinical testing, accelerating the progression to clinical efficacy trials and reducing the cost of drug development by at least 40%. The Seleem Laboratory has discovered and studied the mechanism of action of multiple FDA-approved drugs and clinical molecules to target multidrug-resistant pathogens. This work began with the drug simvastatin, a project that was funded with the assistance of a highly competitive Incentive Grant Proposal Category II) (1) . This work evolved into more complex studies (2-8). The Seleem lab was the first to identify the antimicrobial mechanism of action of several FDA-approved drugs and repurpose them for potential clinical trials(2-8). We are currently using different animal models in combination with molecular techniques to explore the potential of repurposed drugs to treat bacterial and fungal infections. These projects have been primarily funded by National Institutes of Health R56 and R01 grants.
Antimicrobial Drug Discovery
In the area of de novo drug discovery, Dr. Seleem has collaborated with researchers at Purdue University as well as other national and international colleagues for antibacterial and antifungal drug discovery. Dr. Seleem currently has multiple collaborative de novo drug discovery projects with researchers nationally and internationally(15, 19-31).
Neisseria gonorrhoeae
We have an active drug discovery program with a focus on compounds active against Neisseria gonorrhoeae.
We are engaged in research with several collaborators to develop, characterize and test novel therapeutic strategies for drug resistance pathogens.
Clostridium difficile
We have an active drug discovery program with a focus on compounds active against Clostridium difficile(32).
We are engaged in research with several collaborators to develop, characterize and test novel therapeutic strategies for drug resistance pathogens.
Antifungal Drug Discovery
Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of Candida, Cryptococcus, and Aspergillus. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. Our group is interested in antifungal drug discovery including testing and screening(15), identifying mechanism of action(16), reverting azole resistance(17), emerging fungal pathogen candida auris(18) and fungal biofilm (15).
Changing the Culture of Bacterial Culture
Every year, more than one million people in the United States are affected by bloodstream infections (BSI) and about 270,000 die as a result. Blood specimens are obtained and cultured for 1 to 5 days to determine the identity of existing pathogens and susceptibility to various antimicrobial agents. In an attempt to treat the infection before results of the culture come back, doctors often give patients antibiotics cocktail, hoping that one of the medications in the bunch will cure the patient. Often, it doesn’t, and sometimes patients are harmed by taking drugs they didn’t need. This practice also contributes to the increasing prevalence of antimicrobial resistance. For every hour of delay in starting correct antimicrobial therapy, the risk of death for a given patient with sepsis increases by 6% to 10%. Dr. Seleem has collaborated with Dr. Ji-Xin Cheng, Moustakas Chair Professor in Photonics and Optoelectronics at Boston University and world-wide leader in coherent Raman scattering microscopy, to focus on bloodstream infections and drug resistance. Drs. Seleem and Cheng with a $1.7 million grant from the National Institutes of Health are developing a microsecond-scale stimulated Raman spectroscopic imaging platform to enable in situ identification of a single bacterium/fungus in a complex environment at sub-micron resolution; along with early detection of its response to an antimicrobial drug(13, 14). This development will shift the paradigm of BSI diagnosis from a time-consuming, cultivation-dependent procedure to a culture-independent, in situ approach. Further clinical translation of the proposed technology would save patients’ lives with the early diagnosis of BSI and accurate profiling of a pathogen’s susceptibility to antimicrobials.