Biology subjects

Jenkins, C. H.

Publications and source records attributed to Jenkins, C. H..

3 recordsLinked to original sources

bioRxiv2026

Yersinia pseudotuberculosis employs a multifaceted strategy to survive antimicrobials

Microbes have evolved a variety of strategies to survive exposure to naturally occurring and synthetic antimicrobials. These strategies have been investigated extensively in model bacterial organisms, whereas less is known about under explored pathogenic bacteria such as bacteria within the Yersinia genus. In this study we investigated the inhibitory effect and bactericidal activity of antibiotics from five different classes and of the disinfectant hydrogen peroxide against Yersinia pseudotuberculosis, the ancestral species from which Yersinia pestis and Yersinia enterocolitica have emerged. We found that Y. pseudotuberculosis is able to survive exposure to clinical antibiotics and disinfectants by employing a variety of strategies, with persisters and the Eagle effect playing a role in survival to quinolones, tolerance playing a role in survival to ceftriaxone and overexpression of catalases and peroxidases playing a role in survival to hydrogen peroxide. Our findings suggest that future research should focus on informing new, effective ways to treat infections caused by Yersinia species. IMPORTANCEAntimicrobial resistance is routinely investigated by measuring the minimum inhibitory concentration of antimicrobials needed to stop microbial growth. Here we show that the bacterial pathogen Yersinia pseudotuberculosis is not killed when antibiotics and disinfectants are used at these concentrations and that, in some cases, increasing antibiotic concentrations decreases their activity against this bacterium, therefore posing a potential risk to human and animal health.

microbiology↗

bioRxiv2025

Cryo-EM reveals multiple mechanisms of ribosome inhibition by doxycycline

Antimicrobial resistance is driving the search for new antibiotics and a greater understanding of their mechanism of action. Doxycycline is amongst the most-prescribed antimicrobials. It demonstrates a particularly low minimum inhibitory concentration against the zoonotic pathogen Coxiella burnetii. Doxycycline canonically targets the bacterial ribosome by blocking tRNA binding at the decoding centre (A-site) of the small subunit. Using cryo electron-microscopy, we analysed doxycycline binding to C. burnetii and Escherichia coli ribosomes. Both structures reveal unexpected binding at the exit tunnel in the large subunit. In C. burnetii three doxycycline molecules stack to block the tunnel. In E. coli one doxycycline molecule triggers a major uncharacterised conformation of the ribosome. This fundamentally reorganises the peptidyl transferase centre and blocks tRNA binding, challenging the concept that this region is largely static. We identify a new ribosomal protein in the C. burnetii large subunit and characterise an additional member of the prokaryotic ribosome hibernation promoting factor family. These insights into ribosome function and antibiotic action may aid the development of new ribosome inhibitor antibiotics.

biochemistry↗

bioRxiv2025

Structure and catalytic mechanism of methylisocitrate lyase, a potential drug target against Coxiella burnetii

We present a comprehensive investigation into the catalytic mechanism of methylisocitrate lyase, a potential drug target candidate against the zoonotic pathogen Coxiella burnetii, the causative agent of Q fever and a federal select agent. Current treatment regimens are prolonged, often with incomplete clearance of the pathogen. We utilised a structure-based bioinformatics pipeline to identify methylisocitrate lyase as a candidate therapeutic target against C. burnetii from a list of essential genes. Wild-type C. burnetii methylisocitrate lyase has a kcat of 32,000 s-1 (compared to 105 s-1 for Salmonella enterica) and isocitrate inhibits with a KI of 6 mM. We have determined the previously uncharacterised substrate-bound structure of this enzyme family, alongside product and inhibitor-bound structures. These structures of wild-type enzyme reveal that in the active state the catalytic C118 is positioned 2.98 [A] from O5 of methylisocitrate and Arg152 moves towards the substrate relative to the inhibitor bound structure. Analysis of structure-based mutants reveals that Arg152 and Glu110 are both essential for catalysis. We suggest that Arg152 acts as the catalytic base that initiates the methylisocitrate lyase reaction. These results deepen our understanding of the catalytic mechanism of methylisocitrate lyase and could aid the development of new therapeutics against C. burnetii.

biochemistry↗