Signature Research Projects
Drug Repurposing for Antimicrobial Resistance
Drug repurposing is gaining significant momentum due to its advantages, such as bypassing extensive preclinical testing, expediting the progression to clinical efficacy trials, and reducing drug development costs by at least 40%.
At the forefront of this field, the Seleem Laboratory has undertaken groundbreaking research on the mechanism of action of various FDA-approved drugs and clinical molecules to target multidrug-resistant pathogens.
As the research evolved, the lab embarked on more intricate studies, becoming the pioneer in identifying the antimicrobial mechanism of action of several FDA-approved drugs and repurposing them for potential clinical trials.
Currently, our focus lies in utilizing different animal models in conjunction with molecular techniques to assess the potential of repurposed drugs in treating bacterial and fungal infections. The successful continuation of these projects owes much to the support received from National Institutes of Health.
Antimicrobial Drug Discovery
In the realm of de novo drug discovery, Seleem lab has been an active collaborator with researchers and esteemed colleagues from various national and international institutions, in the pursuit of antibacterial and antifungal drug discovery.
Currently, Seleem lab is engaged in multiple collaborative de novo drug discovery projects with researchers both nationally and internationally, furthering the collective effort to combat infectious diseases.
Neisseria gonorrhoeae
Our research team maintains an active drug discovery program with a specific emphasis on identifying compounds that show activity against Neisseria gonorrhoeae.
In collaboration with several partners, we are deeply involved in researching, developing, characterizing, and testing innovative therapeutic approaches to combat drug-resistant pathogens. By working together with our collaborators, we aim to contribute significantly to the advancement of effective treatments against challenging infectious diseases.
Neisseria gonorrhoeae
In our gonococcal infection mouse model, we assessed the in vivo efficacy of a single oral dose of compound 1cv against two strains: A) azithromycin-resistant N. gonorrhoeae AR-0181, and B) ceftriaxone-resistant N. gonorrhoeae WHO-X
The data were analyzed via a two-way ANOVA followed by post-hoc Dunnett’s test for multiple comparisons. Asterisks (*) indicate a statistically significant difference for treatment groups compared to the vehicle, while the symbol (^) indicates a statistically significant difference for compound 1cv as compared to a single intraperitoneal dose of 15 mg/kg ceftriaxone (P<0.05).
Clostridium difficile
We have an active drug discovery program with a focus on Clostridium difficile.
Efficacy of auranofin in treatment of Clostridioides difficile infection in hamsters. Hamsters were treated with auranofin, vancomycin (20 mg/kg), or the vehicle for 5 days after infection with C. difficile UNT103-1. Kaplan–Meier survival curves were analyzed using a log-rank (Mantel–Cox) and Gehan–Breslow–Wilcoxon tests (P < 0.05). An asterisk (*) denotes a statistically significant difference between hamsters treated with either auranofin or vancomycin in comparison with the vehicle-treated hamsters.
Clostridium difficile
Auranofin protects mice against Clostridioides difficile infection. Mice were treated with auranofin (0.125 mg/kg, 0.25 mg/kg, and 0.5 mg/kg), vancomycin (10 mg/kg), or the vehicle for 5 days after infection with C. difficile spores. Kaplan–Meier survival curves were analyzed using a log-rank (Mantel–Cox) test. Asterisks (*) denote statistical significant difference between mice treated with either auranofin, or vancomycin in comparison with the vehicle-treated mice.
VRE
Burden of VRE (E. faecium HM-952) in the fecal contents of colonized mice. The CFU data were analyzed via a two-way ANOVA with post hoc Dunnett’s test for multiple comparisons. An asterisk (*) indicates a significant difference (P < 0.05) between mice treated with AZM or LZD compared with vehicle. A pound sign (#) indicates a significant difference (P < 0.05) between mice treated with AZM compared to LZD-treated mice.
VRE
Burden of VRE (E. faecium HM-952) in (A) the cecal contents of colonized mice and (B) the ileal contents of colonized mice (collected at sacrifice on day 8). The CFU data were analyzed via a one-way ANOVA with post hoc Dunnett’s test for multiple comparisons. An asterisk (*) indicates a significant difference (P < 0.05) between mice treated with AZM or LZD compared with untreated mice (vehicle). A pound sign (#) indicates a significant difference (P < 0.05) between mice treated with AZM compared to LZD-treated mice.
VRE
In vivo antibacterial activity of auranofin against E. faecium NR-31909 in the murine septicemia model when administered (A) Orally at 0.125 mg/kg, 0.25 mg/kg and 0.5 mg/kg; and (B) Subcutaneously (S.C.) at 0.0625 mg/kg, 0.125 mg/kg and 0.25 mg/kg compared to the vehicle control and the standard antibiotic linezolid given orally at 20 mg/kg. Mice survival was monitored for 5 days. Results were analyzed for statistical difference utilizing graphpad prism. (*) Denotes significant difference between each treated group and the untreated group (P < 0.05).
MRSA
Mouse model of MRSA systemic infection: Ten mice per group were infected (i.p) with lethal dose of MRSA USA300 and treated orally with auranofin (0.125 or 0.25 mg/kg), linezolid (25 mg/kg), or the vehicle alone for three days (one dose per day). Mice were monitored for five days and the percent survival was calculated. A log rank test was performed using 95% confidence intervals and the statistical significance was calculated in order to compare treated to control groups. P values of (* ≤ 0.05) (**P ≤ 0.01) are considered as significant. Detailed “P” values are listed below. Control vs linezolid (25 mg/kg):0.0001, Control vs auranofin (0.25 mg/kg): 0.0008, Control vs auranofin (0.125 mg/kg): 0.04. (b) Five mice per group were infected (i.p) with non-lethal dose of MRSA USA300 and treated orally with auranofin (0.25 mg/kg), linezolid (25 mg/kg), or the vehicle alone for two days (one dose per day). 24 hours after the last treatment, mice were euthanized and their spleen and liver were excised and homogenized in TSB to count viable MRSA colonies. The number of CFU from each mouse is plotted as individual points. Statistical analysis was conducted using the two-tailed Student’s ‘t’ test and P values of (* ≤ 0.05) are considered as significant. Detailed “P” values are listed below. Spleen: Control vs linezolid (25 mg/kg):0.0173, Control vs auranofin (0.25 mg/kg): 0.0153. Liver: Control vs linezolid (25 mg/kg):0.0481, Control vs auranofin (0.25 mg/kg): 0.0178.
Candida auris mouse model of disseminated candidiasis
In vivo efficacy of the itraconazole (ITC)-atazanavir (ATV)-ritonavir (RTV) combination in a murine model of C. auris disseminated infection. Female CD-1 mice (n = 8) were infected with azole-resistant C. auris AR0390 and then treated with either the vehicle control, ITC (5 mg/kg), ATV-RTV (90 and 30 mg/kg, respectively), or ITC-ATV-RTV (5, 90, and 30 mg/kg, respectively). Statistical difference was measured via one-way analysis of variance (ANOVA) with the post hoc Dunnett’s test for multiple comparisons. The asterisk (*) denotes statistical significance of the combination treatment (P < 0.01) compared to the untreated control. The pound sign (#) denotes statistical significance (P < 0.01) compared to the ITC-treated group.
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.