Biology subjects

Seth-Smith, H. M. B.

Publications and source records attributed to Seth-Smith, H. M. B..

3 recordsLinked to original sources

bioRxiv2026

Machine learning-guided discovery of a conserved plasmid proteomic signature enables MALDI-TOF MS detection of pOXA-48-carrying Enterobacterales

OXA-48 carbapenemases are among the most widespread and important resistance mechanisms in Enterobacterales. Yet detecting carbapenemases by conventional workflows necessitates additional testing, thus delaying optimization of therapy and implementation of infection control measures. Here, we present a machine learning approach that identifies the conserved pOXA-48 plasmid directly from routine MALDI-TOF spectra acquired for species identification. The model detects pOXA-48 carriers with an AUROC of 0.96-0.98 across two independent hospital cohorts and instrument platforms, indicating near-perfect discrimination. Using bottom-up proteomics, plasmid conjugation, and plasmid curing, we link the discriminative MALDI-TOF spectral features to proteins encoded on pOXA-48, with DUF1496 domain-containing protein producing the most discriminative spectral feature. Our approach reframes the resistance prediction task from inferring a resistance phenotype to detecting a conserved plasmid through its expressed proteomic signature and has the potential to enable rapid MALDI-TOF MS-based diagnostics for a wide range of plasmid-based resistance determinants.

microbiology↗

bioRxiv2023

Ancient methicillin-resistant Staphylococcus aureus: expanding current knowledge using molecular epidemiological characterization of a Swiss legacy collection

Few methicillin-resistant Staphylococcus aureus (MRSA) from the early years of its global emergence have been sequenced. Knowledge about evolutionary factors promoting the success of specific MRSA multi-locus sequence types (MLSTs) remains scarce. We aimed to characterize a legacy MRSA collection isolated from 1965 to 1987 and compare it against publicly available international and local genomes. We accessed 451 ancient (1965-1987) Swiss MRSA isolates, stored in the Culture Collection of Switzerland. We determined phenotypic antimicrobial resistance (AMR) and performed Illumina short-read sequencing on all isolates and long-read sequencing on a selection with Oxford Nanopore Technology. For context, we included 103 publicly available international genomes from 1960 to 1992 and sequenced 1207 modern Swiss MRSA isolates from 2007 to 2022. We analyzed the core genome (cg)MLST and predicted SCCmec cassette types, AMR, and virulence genes. Among the 451 ancient Swiss MRSA isolates, we found 17 sequence types (STs) of which 11 have been previously described. Two STs were novel combinations of known loci and six isolates carried previously unsubmitted MLST alleles, representing five new STs (ST7843, ST7844, ST7837, ST7839, and ST7842). Most isolates (83% 376/451) represented ST247-MRSA-I isolated in the 1960s, followed by ST7844 (6% 25/451), a novel single locus variant (SLV) of ST239. Analysis by cgMLST indicated that isolates belonging to ST7844-MRSA-III cluster within the diversity of ST239-MRSA-IIII. Early MRSA were predominantly from clonal complex (CC) 8. From 1980 to the end of the 20th century we observed that CC22 and CC5 as well as CC8 were present, both locally and internationally. The combined analysis of 1761 ancient and contemporary MRSA isolates across more than 50 years uncovered novel STs and allowed us a glimpse into the lineage flux between Swiss and international MRSA across time.

microbiology↗

bioRxiv2017

Population-based analysis of ocular Chlamydia trachomatis in trachoma-endemic West African communities identifies genomic markers of disease severity

Chlamydia trachomatis (Ct) is the most common infectious cause of blindness and bacterial sexually transmitted infection worldwide. Using Ct whole genome sequences obtained directly from conjunctival swabs, we studied Ct genomic diversity and associations between Ct genetic polymorphisms with ocular localization and disease severity in a treatment-naive trachoma-endemic population in Guinea Bissau, West Africa. All sequences fall within the T2 ocular clade phylogenetically. This is consistent with the presence of the characteristic deletion in trpA resulting in a truncated non-functional protein and the ocular tyrosine repeat regions present in tarP associated with ocular tissue localization. We have identified twenty-one Ct non-synonymous single nucleotide polymorphisms (SNPs) associated with ocular localization, including SNPs within pmpD (OR=4.07, p*=0.001) and tarP (OR=0.34, p*=0.009). Eight SNPs associated with disease severity were found in yjfH (rlmB) (OR=0.13, p*=0.037), CTA0273 (OR=0.12, p*=0.027), trmD (OR=0.12, p*=0.032), CTA0744 (OR=0.12, p*=0.041), glgA (OR=0.10, p*=0.026), alaS (OR=0.10, p*=0.032), pmpE (OR=0.08, p*=0.001) and the intergenic region CTA0744-CTA0745 (OR=0.13, p*=0.043). This study demonstrates the extent of genomic diversity within a naturally circulating population of ocular Ct, and the first to describe novel genomic associations with disease severity. These findings direct investigation of host-pathogen interactions that may be important in ocular Ct pathogenesis and disease transmission.

genomics↗