Biology subjects

Lacey, J. A.

Publications and source records attributed to Lacey, J. A..

5 recordsLinked to original sources

bioRxiv2026

Antifungal resistance mechanisms and nosocomial transmission of Nakaseomyces glabratus: genomic investigation and observational study in Melbourne, Australia

Nakaseomyces glabratus (Candida glabrata) is a WHO high-priority fungal pathogen associated with fungal antimicrobial resistance (fAMR). Given nosocomial transmission occurs sporadically, resistant strains could be transmitted, a concern for critically ill patients. We conducted a genomic investigation and retrospective observational study of N. glabratus to identify any nosocomial transmission of fAMR and understand resistance mechanisms and clinical and demiological factors among patients at a quaternary hospital in Melbourne, Australia. We selected stored N. glabratus with and without fAMR associated with similar patient clinical characteristics and performed whole genome sequencing. Clinical and epidemiological data were extracted from medical records. Phylogenetic, mutational, copy-number variation (CNV) and mitochondrial genomic analyses were performed, with a focus on the fAMR gene PDR1. Of 54 isolates collected over seven years, 20 (37%) were fluconazole-resistant and four (7%) had elevated flucytosine minimum inhibitory concentrations (MICs) (range 2-32 g/ml). There were no significant clinical differences between patients with and without fluconazole resistance. Most (55%) fluconazole-resistant isolates carried PDR1 mutations. Resistance was distributed throughout the phylogeny suggesting predominantly independent acquisition. However, a cluster of four resistant isolates with the same PDR1 mutation suggested nosocomial transmission. One probable ERG11 gene duplication, and two petite variants with apparent mitochondrial genomic deletions, were seen in association with fluconazole resistance. In this study, we identified a small probable nosocomial fAMR transmission cluster, and novel variants in PDR1, ERG11 and FCY2 associated with fAMR phenotypes. Future study should confirm functional impacts and systematically investigate for nosocomial transmission of resistance, including colonisation states.

microbiology↗

bioRxiv2026

Incremental AMR acquisition driving successive genotype replacements and the rise of extensively drug resistant (XDR) Shigella sonnei in Australia over 20 years.

BackgroundIn Australia, the burden of shigellosis is predominantly in returning travellers or in men who have sex with men (MSM). Here, we combine genomic data with comprehensive epidemiological data on sexual exposure and international travel to explore population dynamics of Shigella sonnei and the expansion of multi-drug resistant (MDR) and extensively drug-resistant (XDR) sub-lineages. MethodsA population-level study of all cultured Shigella sonnei isolates in the state of Victoria, Australia, was undertaken between January 2002 and December 2024. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatic analyses of 1,305 Shigella sonnei isolates were performed at the Microbiological Diagnostic Unit Public Health Laboratory. Enhanced metadata on source attribution including travel and sexual exposure were collected through surveillance forms or by interviews. ResultsThis study highlights significant shifts in Shigella sonnei cases in Victoria from sensitive strains to MDR and then XDR, particularly in the MSM-associated groups but also associated with a large point source outbreak. We describe an historical pattern of shifting genotype prevalence, and replacement to more varied and higher proportions of antimicrobial resistance over the last decade, resulting in the establishment of two distinct but highly concerning XDR sub-lineages within Victoria. ConclusionsOur genomic-epidemiological analyses highlight that drug-resistant Shigella sonnei remains an ongoing public health threat, and the importance of ongoing surveillance. We determined local evolutionary trajectories and identified expanding sub-lineages that informed shifts in clinical management and antimicrobial recommendations over time, including the use of azithromycin and carbapenems. Placing these local dynamics within the broader global epidemiology, we link how regional evolution interconnects with international dissemination, proving valuable context for guiding local, national and global strategies for prevent outbreaks and antimicrobial resistance.

microbiology↗

bioRxiv2023

Genetic heterogeneity in the Salmonella Typhi Vi capsule locus: A population genomic study from Fiji

Typhoid fever is endemic in many parts of the world and remains a major public health concern in tropical and sub-tropical developing nations, including Fiji. To address high rates of typhoid fever, the Northern Division of Fiji is implementing a mass vaccination with typhoid conjugate vaccine (Vi-polysaccharide conjugated to tetanus toxoid) as a public health control measure in 2023. In this study we define the genomic epidemiology of S. Typhi in the Northern Division prior to island-wide vaccination, sequencing 85% (n=419) of the total cases from the Northern Division and Central Divisions of Fiji that occurred in the period 2017-2019. We found elevated rates of nucleotide polymorphisms in tviD and tviE genes (responsible for Vi-polysaccharide synthesis) relative to core genome levels within the Fiji endemic S. Typhi genotype 4.2. Expansion of these findings within a globally representative database of 12,382 S. Typhi (86 genotyphi clusters) showed evidence of convergent evolution of the same tviE mutations across the S. Typhi population, indicating that tvi selection has occurred both independently and globally. The functional impact of tvi mutations on the Vi-capsular structure and other phenotypic characteristics are presently unknown, yet commonly occurring tviE polymorphisms localise adjacent to predicted active site residues when overlayed against the predicted TviE protein structure. Given the central role of the Vi-polysaccharide in S. Typhi biology and vaccination, further integrated epidemiological, genomic, and phenotypic surveillance is required to determine the spread and functional implications of these mutations.

microbiology↗

bioRxiv2020

Restricted sequence variation in Streptococcus pyogenes penicillin binding proteins

A recent clinical report has linked Streptococcus pyogenes {beta}-lactam antibiotic resistance to mutations in the Penicillin Binding Protein PBP2x. To determine whether this is an isolated case or reflects a broader prevalence of mutations that might confer reduced {beta}-lactam susceptibility, we investigated the relative frequency of penicillin binding protein (PBP) sequence variation within a global database of 9,667 S. pyogenes isolates. We found that mutations in S. pyogenes PBPs (PBP2x, PBP1a, PBP1b and PBP2a) occur infrequently across this global database with less than 3 amino acid changes differing between >99% of the global population. Only 4 of the 9,667 strains contained mutations near transpeptidase active sites. The reported PBP2x T553K substitution was not identified. These findings are in contrast to those of 2,520 S. pneumococcus sequences where PBP mutations are relatively frequent and are often located in key {beta}-lactam binding pockets. These data, combined with the general lack of penicillin resistance reported in S. pyogenes worldwide, suggests that extensive, unknown, constraints restrict S. pyogenes PBP sequence plasticity. These findings imply that while heavy antibiotic pressure may select for mutations in the PBPs, there is currently no evidence of such mutations becoming fixed in the S. pyogenes population nor that mutations are being sequentially acquired in the PBPs. ImportancePenicillin is the first line therapeutic option for Streptococcus pyogenes infections. Despite the global high prevalence of S. pyogenes infections and widespread use of penicillin, reports of resistance to penicillin have been incredibly rare. Recently, penicillin resistance was detected in two clinical S. pyogenes isolates with accompanying mutations in the active site of the penicillin binding protein PBP2x, raising concerns that penicillin resistance may become more widespread. We screened a global database of S. pyogenes genome sequences to investigate the frequency of penicillin binding protein (PBP) mutations, identifying that PBP mutations are uncommon relative to Streptococcus pneumoniae. These findings support clinical observations that penicillin resistance is rare in S. pyogenes, and suggest that there are considerable constraints on S. pyogenes PBP sequence variation.

microbiology↗

bioRxiv2019

Epidemiological consequences of enduring strain-specific immunity requiring repeated episodes of infection

Group A Streptococcus (GAS) skin infections are caused by a diverse array of strain types and are highly prevalent in Indigenous and other disadvantaged populations. The role of strain-specific immunity in preventing GAS infections is poorly understood, representing a critical knowledge gap in vaccine development. A recent GAS murine challenge study showed evidence that sterilising strain-specific and enduring immunity required two skin infections by the same GAS strain within three weeks. This mechanism of developing enduring immunity may be a significant impediment to the accumulation of immunity in populations.\n\nWe used a mathematical model of GAS transmission to investigate the epidemiological consequences of enduring strain-specific immunity developing only after two infections with the same strain within a specified interval. Accounting for uncertainty when correlating murine timeframes to humans, we varied this maximum inter-infection interval from 3 to 420 weeks to assess its impact on prevalence and strain diversity. Model outputs were compared with longitudinal GAS surveillance observations from northern Australia, a region with endemic infection. We also assessed the likely impact of a targeted strain-specific multivalent vaccine in this context.\n\nOur model produced patterns of transmission consistent with observations when the maximum inter-infection interval for developing enduring immunity was 19 weeks. Our vaccine analysis suggests that the leading multivalent GAS vaccine may have limited impact on the prevalence of GAS in populations in northern Australia if strain-specific immunity requires repeated episodes of infection.\n\nOur results suggest that observed GAS epidemiology from disease endemic settings is consistent with enduring strain-specific immunity being dependent on repeated infections with the same strain, and provide additional motivation for relevant human studies to confirm the human immune response to GAS skin infection.\n\nAuthor summaryGroup A Streptococcus (GAS) is a ubiquitous bacterial pathogen that exists in many distinct strains, and is a major cause of death and disability globally. Vaccines against GAS are under development, but their effective use will require better understanding of how immunity develops following infection. Evidence from an animal model of skin infection suggests that the generation of enduring strain-specific immunity requires two infections by the same strain within a short time frame. It is not clear if this mechanism of immune development operates in humans, nor how it would contribute to the persistence of GAS in populations and affect vaccine impact. We used a mathematical model of GAS transmission, calibrated to data collected in an Indigenous Australian community, to assess whether this mechanism of immune development is consistent with epidemiological observations, and to explore its implications for the impact of a vaccine. We found that it is plausible that repeat infections are required for the development of immunity in humans, and illustrate the difficulties associated with achieving sustained reductions in disease prevalence with a vaccine.

epidemiology↗