Biology subjects

Moyo, S. J.

Publications and source records attributed to Moyo, S. J..

5 recordsLinked to original sources

bioRxiv2026

Effects of different concentrations and combinations of antibiotics on the dynamics of intracellular transposition in Escherichia coli

The use of antimicrobial compounds in humans, animals and in agriculture leads to environmental antimicrobial contamination through domestic, industrial and agricultural wastewater. Efforts have been made to perform environmental risk assessments based on the potential of these compounds to select for antimicrobial resistance (AMR) at certain concentrations in bacteria. This has resulted in predicted no effect concentrations (PNEC) which determine the minimum thresholds required to select for resistance. However, the effects of these compounds on intracellular transposition within bacterial isolates, a major driver of AMR, have not been previously assessed. Here, we assess the effect of differing sub-inhibitory concentrations of the third-generation cephalosporin, ceftriaxone, on the rate of intracellular transposition in combination with colistin and kanamycin. Two triple replicons systems (RS1 and RS2) were developed to assess this, each containing a chromosome, plasmid and entrapment vector. We show that sub-inhibitory concentrations of ceftriaxone exert hormetic effects on the intracellular transposition rate in RS1 and a steady linear increase in RS2. This defines a predicted no effect concentration for transposition (PNECT) for ceftriaxone as 320 ng/L in RS1 and 3200 ng/L in RS2. This provides a minimum threshold for the environmental impact of ceftriaxone on biological systems at the sub-cellular scale, which is applicable to industrial standards of waste management, where consideration of ecological impact is central.

microbiology↗

bioRxiv2026

Covalent Inhibition of New Delhi Metallo-β-Lactamases NDM-1 and NDM-5 by 3-Bromopyruvate

Resistance to {beta}-lactam antibiotics, including carbapenems, mediated by metallo-{beta}-lactamases (MBLs), including the New Delhi metallo-{beta}-lactamase (NDM) MBL subfamily, is increasing. No MBL inhibitors are currently approved for clinical use with most reported MBL inhibitors are metal ion chelators, acting either at the Zn(II) ion active site and/or in solution. The hexokinase inhibitor 3-bromopyruvate (3-BP) is reported to inhibit NDM-1. We found that 3-BP selectively restored the antimicrobial activity of meropenem against carbapenem resistant Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii strains, obtained from clinical and environmental isolates from Tanzania and Malawi, containing genes that encode NDM-1 or NDM-5, but not against strains containing genes encoding for serine {beta}-lactamases. Mass spectrometry studies with NDM-1 and NDM-5 support a mechanism involving covalent reaction of 3-BP with an active site cysteine residue. The results will promote work on the development of covalently reacting MBL inhibitors, a strategy that has been successful for inhibition of the nucleophilic serine {beta}-lactamases.

microbiology↗

bioRxiv2026

In vivo de-amplification of a multi-resistance pseudo-compound transposon in Escherichia coli

The rapid expansion of antimicrobial resistance (AMR) among Gram-negative pathogens presents a major clinical challenge, particularly in vulnerable populations such as infants. The dissemination of resistance is often mediated by mobile genetic elements (MGEs) that can mobilise antimicrobial resistance genes (ARGs) both within and between genomes. The insertion sequence (IS) IS26, is a MGE with the ability to replicate itself and associated ARGs, create translocatable units (TU), and produce tandem arrays of ARGs. Here we present the 18-week in vivo evolution of a community-acquired multi-drug resistant (MDR) Escherichia coli colonising an infant gut, characterised by a de-amplification of an IS26-mediated tandem array of ARGs. The hybrid-assembled ancestral and descendant strain genomes show an evolutionary rate of 10.22 SNPs per genome per year. Independent analysis of the hybrid genome assembly, and of Oxford Nanopore Technologies (ONT) and Illumina read-mapping support the existence of at least five copies of a TU (Tn3-like(tnpA)-tetR-tetA-yedA-{Delta}Tn1721(tnpA) -IS26-aac(6)-Ib-cr-blaOXA-1-{Delta}catB3-IS26) in the ancestor and only one in the descendant. Despite de-amplification, no change in fitness (p = 0.275) and piperacillin-tazobactam susceptibility (TZP) was observed. In contrast, gentamicin susceptibility increased, in the absence of known associated mutations. This study provides insight into IS26-mobility dynamics in vivo and their implications for AMR, within the rapidly changing environment of the neonatal gut.

microbiology↗

bioRxiv2025

Global diversity, predictors, and predictions of AMR evolutionary pathways in Klebsiella pneumoniae

Antimicrobial resistance (AMR) is a substantial and growing global health burden. Understanding, and predicting, its evolution in specific pathogens will help responses across scales from individual patient cases to large-scale policy. Here, we use global data on AMR features, predicted from 47k Klebsiella pneumoniae genomes, with hypercubic transition path sampling to infer the evolutionary pathways by which AMR features in K. pneumoniae (KpAMR) are acquired across 102 countries, territories and areas. We identify "globally consistent" evolutionary behaviours that hold across countries, and "globally divergent" behaviours including carbapenem and fluoroquinolone resistance that vary across countries. We show how these divergent dynamics covary both with public health superregion and drug use policy, and reveal competing evolutionary pathways within and between countries. Using newly-sequenced data across several decades from sub-Saharan Africa, we show that this inferred global roadmap of KpAMR evolution successfully predicts prospective evolutionary dynamics. Together, we hope that the ability to characterize and predict evolutionary dynamics of AMR acquisition, connected to socio-economic and drug policy predictors, will help strengthen our understanding of AMR evolution worldwide. SignificanceAntimicrobial resistance (AMR) occurs when microbial pathogens evolve resistance to the drugs we use to treat them. Our understanding of bacterial genomes and how they confer AMR is constantly expanding through beautiful and powerful work establishing large-scale global datasets. Here, we use emerging machine learning approaches with this genomic data to reveal the evolutionary dynamics that have generated AMR characters in a particular pathogen, Klebsiella pneumoniae (Kp), and how these dynamics are influenced by geography and drug use across the globe. This "natural history" of AMR in Kp makes predictions about which characters will evolve next for a given bacterium, and we validate these predictions with newly-sequenced data from clinical isolates from Africa, providing both past and prospective descriptions of AMR in Kp.

evolutionary biology↗

bioRxiv2025

Genomic comparison of highly related pairs of E. coli and K. pneumoniae isolated from faeces and blood of the same neonatal patients hospitalized with fever in Dar es Salaam, Tanzania

Blood stream infections (BSIs) are a major cause of hospitalisation and death for children under the age of five in sub-Saharan Africa with members of the Gram-negative bacteria Enterobacterales such as Klebsiella pneumoniae and Escherichia coli among the most common causative agents. These bacteria usually colonise the human gastrointestinal (GI) tract which has been identified as a reservoir for invasive infections into extra-intestinal environments such as the urinary tract and bloodstream. In this study we used comparative genomics to compare hybrid genome assemblies of blood and faecal isolates taken from the same patients (all neonates under 19 days old) to determine if the BSI associated bacterial isolates originated in their GI tract. We show that both E. coli and K. pneumoniae likely translocated from the GI tract to the blood in multiple cases of BSI. We also highlight key virulence genes and acquired mutations that are indicative of pathogenic strains capable of BSI. These findings expand our understanding of BSI pathogenesis and could help guide targeted interventions to prevent future BSI infections in neonates.

genomics↗