Julian Hurdle
· PhDVerifiedTexas A&M University · Microbiology and Immunology
Active 2003–2026
About
Professor Julian Hurdle, PhD, is the Director of the Center for Infectious and Inflammatory Diseases (CIID) and the Director of the IBT Postdoctoral Program at Texas A&M University. He is based at the Center for Infectious and Inflammatory Diseases located at 2121 W. Holcombe Blvd, Houston, TX 77030. His role involves leading research efforts in infectious and inflammatory diseases, contributing to the advancement of knowledge in these fields, and overseeing postdoctoral training programs. Further details about his specific research focus, background, and key contributions are not provided on the page.
Research topics
- Microbiology
- Genetics
- Biology
- Gastroenterology
- Medicine
- Surgery
- Internal medicine
Selected publications
bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-06
articleOpen accessAbstract Streptococcus gallolyticus subsp. gallolyticus ( Sgg ) is an opportunistic pathobiont associated with bacteremia, infective endocarditis, and colorectal cancer. However, the genomic diversity of this subspecies and the distribution of key virulence determinants, particularly the type VII secretion system (T7SS), remain poorly characterized. Here, we performed genomic analyses of 76 Sgg strains from diverse geographic and host origins. Core- and pan-genome analyses, multi locus sequence typing, and phylogenetic reconstruction revealed dominant sequence types (STs) that correlate with geographic origin or source of isolation. Furthermore, systematic characterization of the T7SS locus identified five new T7SS subtypes and demonstrated a strong association between T7SS subtype and ST. We further expanded the known repertoire of T7SS LXG domain-containing polymorphic toxins (LXG toxins) in Sgg substantially through genome-wide searches. Distinct distribution patterns were observed for the LXG toxins across the strains. Lastly, our data indicated that T7SS subtype was significantly associated with biofilm formation capacity of Sgg strains. Together, these findings advance our understanding of Sgg genomic diversity, reveal substantial lineage-associated variation in T7SS architecture and effector repertoires, and suggest a previously unrecognized connection between T7SS and biofilm formation in Sgg .
Antimicrobial Agents and Chemotherapy · 2025-12-17
articleOpen accessSenior authorABSTRACT Clostridioides difficile, a leading cause of hospital-acquired diarrhea, exerts its virulence through two co-regulated toxins, TcdA and TcdB. Despite their pivotal roles, the discovery of inhibitors targeting their biosynthesis is underexplored. Here, we present a high-throughput screening (HTS) platform designed to identify toxin synthesis inhibitors (TSIs) that minimally impact bacterial growth. The primary screen utilized a C. difficile reporter strain expressing secreted Nano-luciferase (secNluc) under the tcdA promoter, whereby inhibition of secNluc production indicates toxin biosynthesis inhibition. Screening the Prestwick Chemical Library at 10 and 100 µM identified several compounds that reduced secNluc activity. Through counter-screening, we eliminated compounds that caused spectral interference. Orthogonal dose-response assays assessing the effectiveness of inhibiting toxin production without affecting growth identified meclizine, an antihistamine, as the primary antivirulence candidate. Meclizine was confirmed as a TSI by showing that it reduced TcdA and TcdB protein levels, the cytopathic potential of cultures, and tcdA and tcdB transcription as determined by ELISA, cell-rounding assays, and RT-qPCR, respectively. Meclizine significantly altered central carbon metabolism in C. difficile , upregulating carbohydrate transport systems and the conversion of lactate to pyruvate, while downregulating glycolytic genes. These changes were associated with intracellular accumulation of glucose and pyruvate, metabolites known to negatively impact toxin production. Taken together, our findings underscore the utility of the above HTS platform to identify anti- C . difficile TSIs, which can serve as molecular and cellular probes, as well as chemical starting points for developing novel therapeutics for C. difficile infection.
ACS Bio & Med Chem Au · 2025-11-19
articleOpen accessFusobacterium nucleatum is a Gram-negative anaerobic bacterium ubiquitous in the oral cavity and increasingly recognized for its involvement in diverse clinical conditions, including periodontal disease, inflammatory bowel disease, premature birth, and several forms of cancer. These associations highlight the need for narrow-spectrum antibacterial agents directed against F. nucleatum to avoid disruption of beneficial microflora and limit the rise of antibiotic resistance. Recent studies have identified the fusobacterial fatty acid synthesis pathway (FAS-II) enzyme, enoyl-acyl carrier protein (ACP) reductase, FnFabK, as an essential and promising target for selective antibacterial intervention. However, there is a lack of detailed structural information, which has hindered the validation of FnFabK’s druggability and the discovery of new inhibitors. Here, we present a comprehensive characterization of FnFabK, including its cocrystal structure solved at 2.25 Å resolution and its biochemical and biophysical interactions with a series of potent small-molecule inhibitors. Our analyses revealed that these inhibitors display low to submicromolar activity against FnFabK, with notable selectivity and differential activity when tested against FabK homologues from other bacterial pathogens. Importantly, the unique structural features of the FnFabK active site, elucidated through these crystallographic studies, provide a mechanistic basis for species-specific inhibition. These findings not only validate FnFabK as a druggable target but also furnish critical insights into the design of next-generation narrow-spectrum antibacterial agents.
Antimicrobial Agents and Chemotherapy · 2025-02-21 · 2 citations
articleOpen accessABSTRACT Ibezapolstat (IBZ), a first-in-class antibiotic targeting the PolC-type DNA polymerase III alpha-subunit (PolC) in low G + C bacteria, is in clinical development for the treatment of Clostridioides difficile infection (CDI). In the phase 2 trials, IBZ had potent activity against C. difficile while sparing or causing regrowth of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichales, common commensal low G + C bacteria. The purpose of this study was to utilize in silico approaches to better interpret the narrower than expected IBZ spectrum of activity. IBZ susceptibility to human commensal microbiota was predicted using genomic analysis and PolC phylogenetic tree construction in relation to C. difficile and commensal low G + C bacteria. Protein structure prediction was performed using AlphaFold2 and binding pocket homology modeling was performed using Schrodinger Maestro and UCSF ChimeraX. An amino acid phylogenetic tree identified certain residues that were phylogenetically variant in Lachnospiraceae, Oscillospiraceae, and Erysipelotrichales and conserved in C. difficile . Chemical modeling showed that these residues ablated key PolC•IBZ predicted interactions including two lysine “ gates ” ( CdiPolC Lys1148 and CdiPolC Lys1327) that “ latch ” onto the compound; an “ anchoring ” interaction ( CdiPolC Thr1331) to the central moiety; and a stabilized set of C. difficile sensitizer residues ( CdiPolC Thr1291 and CdiPolC Lys1292) that resulted in the prolonged inhibition of a catalytic residue ( CdiPolC Asp1090). The observed IBZ sparing of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichaceae/Coprobacillaceae was predicted using in silico techniques. Further studies that confirm a PolC structural basis for the IBZ narrower than expected activity are needed to confirm these in silico phylogenetic and chemical modeling data.
Clinical Infectious Diseases · 2024-02-19 · 32 citations
articleOpen accessBACKGROUND: Epidemiologic studies have shown decreasing vancomycin susceptibility among clinical Clostridioides difficile isolates, but the impact on patient outcomes is unknown. We hypothesized that reduced vancomycin susceptibility would be associated with decreased rates of sustained clinical response (SCR). METHODS: This multicenter cohort study included adults with C. difficile infection (CDI) treated with oral vancomycin between 2016 and 2021. Clostridioides difficile isolates underwent agar dilution vancomycin susceptibility testing, ribotyping, and Sanger sequencing of the vancomycin resistance vanR gene. Reduced susceptibility was defined as vancomycin minimum inhibitory concentration (MIC) >2 μg/mL. The primary outcome was 30-day SCR; secondary outcomes were 14-day initial cure, 30-day recurrence, and 30-day mortality. Exploratory analysis assessed the association between the VanR Thr115Ala polymorphism, susceptibility, and outcomes. RESULTS: A high proportion (34% [102/300]) of C. difficile isolates exhibited reduced vancomycin susceptibility (range, 0.5-16 μg/mL; MIC50/90 = 2/4 μg/mL). Ribotype 027 accounted for the highest proportion (77.4% [41/53]) of isolates with reduced vancomycin susceptibility. Overall, 83% (249) of patients achieved 30-day SCR. Reduced vancomycin susceptibility was associated with lower rates of 30-day SCR (76% [78/102]) than vancomycin-susceptible strains (86% [171/198]; P = .031). A significantly lower rate of 14-day initial cure was also observed among individuals infected with strains with reduced vancomycin susceptibility (89% vs 96%; P = .04). Reduced susceptibility remained an independent predictor of 30-day SCR in multivariable modeling (odds ratio, 0.52 [95% confidence interval, .28-.97]; P = .04). CONCLUSIONS: Reduced vancomycin susceptibility in C. difficile was associated with decreased odds of 30-day SCR and lower 14-day initial cure rates in the studied patient cohort.
ACS Infectious Diseases · 2024-04-10 · 6 citations
articleOpen accessSenior authorCorrespondingFabK is an essential enzyme that is amenable to drug targeting for the discovery and development of narrow-spectrum antimicrobial agents.
Open Forum Infectious Diseases · 2024-10-10 · 6 citations
articleOpen accessCorrespondingAbstract Background Reduced vancomycin (VAN) susceptibility in clinical Clostridioides difficile isolates is correlated with poor clinical outcomes. However, factors associated with infection with these strains are unknown. The goal of this study was to determine risk factors for reduced VAN susceptibility among clinical isolates of C. difficile. Methods This multicenter cohort study included adults with C. difficile infection (CDI) between 2016 and 2021. Clinical C. difficile isolates underwent agar dilution VAN susceptibility testing and ribotyping. Reduced susceptibility was defined as a minimum inhibitory concentration (MIC) > 2 µg/mL. Medical charts were reviewed for host, pathogen, and hospital characteristics and assessed for predictors of reduced VAN susceptibility. Results Five hundred and ninety-four hospitalized patients with CDI between 2016 and 2021 (female: 57%, age >65 years: 55%, White/non-Hispanic: 59%, nonsevere CDI episode: 53%) were identified. Of 594 isolates, 173 (29%) had reduced VAN susceptibility (MIC50: 2 µg/mL, MIC90: 4 µg/mL). In multivariable analysis, ribotype (RT) 027 (odds ratio [OR]: 13.4; 95% confidence interval [CI], 7.7–23.4; P < .0001) and RT 255 (OR: 2.9; 95% CI, 1.4–6.1; P = .005) were positively associated with reduced VAN susceptibility whereas RT 014–020 (OR: 0.41; 95% CI, 0.21–0.80; P = .0092) was more likely to be susceptible to VAN. The prevalence of strains with reduced VAN susceptibility increased over time (P = .0163). No patient- or hospitalization-specific variable predicted infection with reduced susceptibility strain. Conclusions Certain ribotypes, including RT 027, were the sole independent risk factors for reduced VAN susceptibility. Increased clinical surveillance of these strains, especially RT 027, and their antibiotic susceptibly is warranted to inform prescribing practices.
Journal of Biological Chemistry · 2024-09-27 · 8 citations
articleOpen accessSenior authorToxins TcdA and TcdB are the main virulence factors of Clostridioides difficile, a leading cause of hospital-acquired diarrhea. Despite their importance, there is a significant knowledge gap of druggable targets for inhibiting toxin production. To address this, we screened nonantibiotic phytochemicals to identify potential chemical genetic probes to discover antivirulence drug targets. This led to the identification of 18β-glycyrrhetinic acid (enoxolone), a licorice metabolite, as an inhibitor of TcdA and TcdB biosynthesis. Using affinity-based proteomics, potential targets were identified as ATP synthase subunit alpha (AtpA) and adenine deaminase (Ade, which catalyzes conversion of adenine to hypoxanthine in the purine salvage pathway). To validate these targets, a multifaceted approach was adopted. Gene silencing of ade and atpA inhibited toxin biosynthesis, while surface plasmon resonance and isothermal titration calorimetry molecular interaction analyses revealed direct binding of enoxolone to Ade. Metabolomics demonstrated enoxolone induced the accumulation of adenosine, while depleting hypoxanthine and ATP in C. difficile. Transcriptomics further revealed enoxolone dysregulated phosphate uptake genes, which correlated with reduced cellular phosphate levels. These findings suggest that enoxolone's cellular action is multitargeted. Accordingly, supplementation with both hypoxanthine and triethyl phosphate, a phosphate source, was required to fully restore toxin production in the presence of enoxolone. In conclusion, through the characterization of enoxolone, we identified promising antivirulence targets that interfere with nucleotide salvage and ATP synthesis, which may also block toxin biosynthesis.
Antimicrobial Agents and Chemotherapy · 2024-01-24 · 3 citations
articleOpen accessSenior authorABSTRACT Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired diarrhea, which often stems from disruption of the gut microbiota by broad-spectrum antibiotics. The increasing prevalence of antibiotic-resistant C. difficile strains, combined with disappointing clinical trial results for recent antibiotic candidates, underscores the urgent need for novel CDI antibiotics. To this end, we investigated C. difficile enoyl ACP reductase ( Cd FabK), a crucial enzyme in de novo fatty acid synthesis, as a drug target for microbiome-sparing antibiotics. To test this concept, we evaluated the efficacy and in vivo spectrum of activity of the phenylimidazole analog 296, which is validated to inhibit intracellular Cd FabK. Against major CDI-associated ribotypes 296 had an Minimum inhibitory concentration (MIC 90 ) of 2 µg/mL, which was comparable to vancomycin (1 µg/mL), a standard of care antibiotic. In addition, 296 achieved high colonic concentrations and displayed dosed-dependent efficacy in mice with colitis CDI. Mice that were given 296 retained colonization resistance to C. difficile and had microbiomes that resembled the untreated mice. Conversely, both vancomycin and fidaxomicin induced significant changes to mice microbiomes, in a manner consistent with prior reports. Cd FabK, therefore, represents a potential target for microbiome-sparing CDI antibiotics, with phenylimidazoles providing a good chemical starting point for designing such agents.
Antimicrobial Agents and Chemotherapy · 2024-11-06 · 6 citations
reviewOpen accessABSTRACT Fidaxomicin (FDX), an RNA polymerase (RNAP) inhibitor antibiotic, is a guideline-recommended therapy for Clostridioides difficile infection. Mutations associated with reduced FDX minimum inhibitory concentrations (MICs) have been identified. However, the molecular characterization of these mutations on FDX binding and the development of FDX resistance have not been studied. The purpose of this systematic review was to identify FDX resistance in C. difficile isolates and determine whether single nucleotide polymorphisms associated with increased FDX MIC aligned with the RNAP binding pocket interacting residues. A systematic literature search was done in PubMed (1991–2023) with identified articles and their bibliographies searched for papers that included C. difficile genetic mutations and increased FDX MIC. Visualization of FDX-RNAP interactions was performed on Schrödinger Maestro using the publicly available C. difficile RNAP with fidaxomicin sequence (code 7L7B) on the Protein Data Bank. Seven articles were identified after applying inclusion and exclusion criteria. The most common mutation in clinical and laboratory isolates was at position V1143 of the β subunit, which accounted for approximately 50% of the identified mutations. Most other mutations occurred within the β′ subunit of RNAP. Approximately one-third of the identified mutation aligned directly with FDX interacting residues with C. difficile RNAP (7/20) with most of the remainder occurring within 5 Å of the binding residues. C. difficile strains with elevated FDX MIC align closely with the known RNAP binding residues. These data demonstrate the potential to identify genomic methods to identify emerging FDX resistance.
Recent grants
NIH · $424k · 2019
NIH · $608k · 2019
NIH · $6.0M · 2018–2028
NIH · $1.9M · 2017
Frequent coauthors
- 28 shared
Richard Lee
St. Jude Children's Research Hospital
- 20 shared
Xiaoqian Wu
Chinese Academy of Medical Sciences & Peking Union Medical College
- 18 shared
Dianqing Sun
- 16 shared
Kevin W. Garey
University of Houston
- 14 shared
Kirk E. Hevener
University of Tennessee Health Science Center
- 12 shared
Anne J Gonzales-Luna
University of Houston
- 11 shared
Chetna Dureja
Texas A&M Health Science Center
- 10 shared
Ravi K. R. Marreddy
Texas A&M Health Science Center
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