Biology subjects

Seleem, M. N.

Publications and source records attributed to Seleem, M. N..

8 recordsLinked to original sources

bioRxiv2025

Discovery of Novel Probiotic Species to Improve Infant Health

Selecting an appropriate infant formula can be challenging for parents given the wide range of available options, which may lead to suboptimal choices or frequent switching. Our recent studies in mice demonstrated that the maternal microbiota--particularly Limosilactobacillus reuteri present in breast milk--plays a critical role in shaping neonatal immunity by promoting the production of immunoglobulin A (IgA), a key antibody for defense against enteric pathogens. To extend these findings to humans, we analyzed fecal samples from healthy breastfed infants using shotgun metagenomic sequencing combined with whole-bacterial-cell ELISA to assess associations between specific taxa and pathogen-reactive IgA. We found that members of the Oscillibacter species (including Oscillibacter sp. KLE1728, KLE1745, PC13, PEA192, and O. valericigenes) and Morganella (e.g., M. morganii, Morganella sp. EGD-HP17, and Morganella sp. HMSC11D09) were strongly correlated with IgA responses against Salmonella and Shigella. In contrast, IgA reactive to enterohemorrhagic Escherichia coli (EHEC) was associated with other genera, including Staphylococcus. Notably, Lactobacillus species (L. bombi, L. kefiri, L. equi, and L. rhamnosus) were consistently linked to elevated IgA responses against Salmonella, Shigella, and EHEC. Moreover, levels of anti-Salmonella and anti-Shigella IgA were positively correlated with the use of infant formula containing prebiotic fibers or human milk oligosaccharides (5-HMO). Collectively, these findings highlight novel commensal taxa with potential as probiotic candidates to guide the development of next-generation infant formulas aimed at enhancing mucosal immunity and supporting infant health. ImportanceEarly-life nutrition shapes immune maturation, yet the microbial factors driving mucosal antibody responses remain poorly defined. Through integrated metagenomic and IgA profiling, this study identifies commensal taxa, particularly Lactobacillus, Oscillibacter, and Morganella, associated with pathogen-specific IgA in infants. These taxa may enhance mucosal defense against enteric pathogens, revealing key microbial contributors to early immune development. The findings provide a foundation for designing next-generation infant formulas that leverage targeted probiotics or prebiotics to promote protective IgA responses and gut health.

microbiology↗

bioRxiv2025

Repurposing Antibacterial Drugs and Clinical Molecules to Combat Vancomycin-Resistant Enterococci (VRE)

Vancomycin-resistant enterococci (VRE) is a growing threat to public health due to its increasing prevalence and limited treatment options. The urgent need for alternative therapeutics necessitates novel strategies such as drug repurposing to identify effective antimicrobial agents. In this study, we screened a library of 1,135 antibacterial compounds to identify candidates with activity against VRE. A total of 58 active compounds were identified, with ridinilazole and CRS3123 emerging as the most promising hits. Both compounds exhibited potent antibacterial activity in the nanomolar range against multiple Enterococcus species, including vancomycin-resistant and vancomycin-sensitive E. faecium, E. faecalis, E. hirae and E. durans. CRS3123 demonstrated exceptional potency, exhibiting MIC values of <0.007 g/mL against most strains. Ridinilazole exhibited an MIC spectrum of <0.007 to 1 g/mL across all strains, with E. faecium being the most sensitive (MIC: <0.007-0.25 g/mL) and E. faecalis displaying a higher MIC range (0.5-1 g/mL). Time-kill assays indicated that both compounds exhibited bacteriostatic activity comparable to linezolid. Additionally, ridinilazole and CRS3123 displayed low cytotoxicity in Vero cells and no hemolytic activity, suggesting a favorable safety profile. In vivo studies using the C. elegans infection model further confirmed their efficacy, with ridinilazole achieving a 60% reduction in VRE burden, CRS3123 resulting in a 25% reduction, and linezolid demonstrating a 55% reduction. These findings highlight ridinilazole and CRS3123 as promising candidates for further development for managing VRE infections.

microbiology↗

bioRxiv2024

Antiviral Library Screening Leads to Discovery of Novel and Potent Anticlostridial Compounds

Clostridium difficile (C. difficile) is a major cause of nosocomial infections, often associated with individuals who have gut dysbiosis from previous antibiotic therapies. C. difficile infections have a high recurrence rate and impose significant financial and mortality burdens on the healthcare system. Novel anti-C. difficile drugs are urgently needed to treat and reduce the severity and recurrence of infection. In this study, we screened a library of 618 antiviral drugs to identify a potential candidate for repurposing as novel anti-C. difficile treatments. Following our preliminary screening, we identified 9 novel compounds that inhibit C. difficile at a concentration of 16 {micro}M or lower. Among these, 4 antiviral compounds demonstrated the most potent anti-C. difficile activity against a panel of 15 C. difficile isolates, with minimum inhibitory concentrations (MICs) comparable to the drug of choice, vancomycin. These include rottlerin (MIC50 = 0.25 {micro}g/mL), -mangostin (MIC50 = 1 {micro}g/mL), dryocrassin ABBA (MIC50 = 1 {micro}g/mL), and obefazimod (MIC50 = 4 {micro}g/mL). All exhibited minimal to no activity against representative members of the gut microbiota. Interestingly, -mangostin, a natural xanthone derived from the mangosteen fruit, exhibited strong bactericidal action, clearing a high inoculum of C. difficile in less than an hour. All other drugs exhibited bacteriostatic activity. Given the characteristics of these compounds, they show great promise as novel treatments for CDI.

microbiology↗

bioRxiv2022

Fingerprint SRS Imaging Unveils Ergosteryl Ester as a Metabolic Signature of Azole-Resistant Candida albicans

Candida albicans (C. albicans), a major fungal pathogen, causes life-threatening infections in immunocompromised individuals. Fluconazole (FLC) is recommended as first-line therapy for treatment of invasive fungal infections. Yet, the widespread use of FLC has resulted in increased antifungal resistance among different strains of Candida, especially C. albicans, which is a leading source of hospital-acquired infections. Here, by hyperspectral stimulated Raman scattering (hSRS) imaging of single fungal cells in the fingerprint window and pixel-wise spectral unmixing, we report aberrant ergosteryl ester accumulation in azole-resistant C. albicans compared to azole-susceptible species. This accumulation was a consequence of de novo lipogenesis. Lipid profiling by mass spectroscopy identified ergosterol oleate to be the major species stored in azole-resistant C. albicans. Blocking ergosterol esterification by oleate and suppressing sterol synthesis by FLC synergistically suppressed the viability of C. albicans in vitro and limited the growth of biofilm on mouse skin in vivo. Our findings highlight a metabolic marker and a new therapeutic strategy for targeting azole-resistant C. albicans by interrupting the esterified ergosterol biosynthetic pathway. Significance StatementInvasive fungal infections and increasing antifungal resistance are emerging threats to public health with high morbidity and mortality. Despite the advances in azole resistance mechanisms, it remains unclear why some fungal species are intrinsically resistant to or easily acquire resistance to multiple antifungal drugs. Here, using fingerprint SRS microscopy, we uncovered a molecular signature, aberrant ergosteryl ester accumulation, linked to the azole resistance of Candida species. An antifungal treatment strategy combining oleate (inhibitor of ersgosteryl esterification) and azole significantly attenuates the azole resistance and the viability of C. albicans in vitro and in vivo. Our work opens a new way to detect and treat azole-resistant fungal infections by targeting ergosterol metabolism.

microbiology↗

bioRxiv2019

Photo-Disassembly of Membrane Microdomains Revives Conventional Antibiotics against MRSA

Confronted with the rapid evolution and dissemination of antibiotic resistance, there is an urgent need to develop alternative treatment strategies for drug-resistant pathogens. Here, we present an unconventional approach to restore the susceptibility of methicillin-resistant S. aureus (MRSA) to a broad spectrum of conventional antibiotics via photo-disassembly of functional membrane microdomains. The photo-disassembly of microdomains is based on effective photolysis of staphyloxanthin, the golden carotenoid pigment that gives its name. Upon pulsed laser treatment, cell membranes are found severely disorganized and malfunctioned to defense antibiotics, as unveiled by membrane permeabilization, membrane fluidification, and detachment of membrane protein, PBP2a. Consequently, our photolysis approach increases susceptibility and inhibits development of resistance to a broad spectrum of antibiotics including penicillins, quinolones, tetracyclines, aminoglycosides, lipopeptides, and oxazolidinones.\n\nOne Sentence SummaryUsing photons to crash S. aureus cell membrane and its formidable defense against a broad spectrum of antibiotics.

microbiology↗

bioRxiv2019

Repurposing approach identifies phenylpentanol derivatives as potent azole chemosensitizing agents effective against azole-resistant Candida species

The limited number of systemic antifungals and the emergence of azole-resistant Candida species constitute a growing challenge to human medicine. Combinatorial drug therapy represents an appealing approach to enhance the activity of, or restore the susceptibility to current antifungals. Here, we evaluated the fluconazole chemosensitization activity of the Pharmakon 1600 drug library against azole-resistant Candida albicans. We identified 33 non-antifungal drugs that were able to restore susceptibility to fluconazole in an azole-resistant C. albicans. Structural investigation of identified hits revealed phenylpentanol scaffold as a valuable pharmacophore for re-sensitizing azole-resistant Candida species to the effect of current azole antifungal drugs. All phenylpentanol derivatives displayed potent fluconazole chemosensitizing activities ({Sigma}FICI 0.13-0.28) and were able to reduce fluconazoles MIC by 15-31 fold against the tested strain. Particularly pitavastatin displayed the most potent fluconazole chemosensitizing activity ({Sigma}FICI 0.06-0.50). The pitavastatin-fluconazole combination displayed a broad-spectrum synergistic relationship against 90% of the tested strains, including strains of C. albicans, C. glabrata, and C. auris. Moreover, pitavastatin restored the susceptibility of the multidrug-resistant C. auris to the antifungal activities of itraconazole and voriconazole. Additionally, the pitavastatin-fluconazole combination significantly reduced the biofilm-forming abilities of the tested Candida species and successfully reduced the fungal burdens in a Caenorhabditis elegans infection model. Both pitavastatin and the plain phenylpentanol scaffold were able to interfere significantly with Candidas efflux activities as demonstrated by Nile Red efflux assays and flow cytometry. This study presents phenylpentanol derivatives as potent azole chemosensitizers that warrant further investigation.

microbiology↗

bioRxiv2019

Mitofusin 2 regulates neutrophil adhesive migration via suppressing Rac activation

Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (Mfn2) regulates neutrophil homeostasis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue and trapped in the vasculature in zebrafish embryos. Human neutrophil-like cells deficient with MFN2 fail to arrest on activated endothelium under sheer stress or perform chemotaxis. Deletion of Mfn2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mfn2, but not Mfn1, -null mouse embryonic fibroblast cells have altered actin structure and are impaired in wound closure. MFN2-deficient neutrophil-like cells display heightened intracellular calcium levels and Rac activation after chemokine stimulation. Mechanistically, MFN2 maintains mitochondria-ER interaction. Restoring mitochondria-ER tether rescues the chemotaxis defect and Rac activation resulted from MFN2 depletion. Finally, inhibition of Rac restores chemotaxis in MFN2-deficient neutrophils. Altogether, we identified that MFN2 regulates neutrophil migration via suppressing Rac activation and uncovered a previously unrecognized role of MFN2 in regulating the actin cytoskeleton.

cell biology↗

bioRxiv2017

Annihilation of Methicillin-resistant Staphylococcus aureus via Photobleaching of Staphyloxanthin

Given that the dearth of new antibiotic development loads an existential burden on successful infectious disease therapy1, health organizations are calling for alternative approaches to combat methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we report a drug-free photonic approach to eliminate MRSA through photobleaching of staphyloxanthin, an indispensable membrane-bound antioxidant of S. aureus2-5. The photobleaching process, uncovered through a transient absorption imaging study and quantitated by absorption spectroscopy and mass spectrometry, decomposes staphyloxanthin and sensitizes MRSA to reactive oxygen species attack. Consequently, staphyloxanthin bleaching by low-level blue light eradicates MRSA synergistically with external or internal reactive oxygen species. The effectiveness of this synergistic therapy is validated in MRSA culture, MRSA-infected macrophage cells, S. aureus biofilms, and a mouse wound infection model. Collectively, these findings highlight broad applications of staphyloxanthin photobleaching for treatment of MRSA infections.

microbiology↗