Biology subjects

Satola, S. W.

Publications and source records attributed to Satola, S. W..

3 recordsLinked to original sources

bioRxiv2026

Heteroresistance in Enterococcus faecalis is prevalent for key antibiotics and mainly caused by mutations

Heteroresistance (HR), the coexistence of a rare resistant subpopulation within a predominantly susceptible bacterial population, is a clinically relevant problem. The resistant subpopulation often escapes detection by standard susceptibility testing, which can lead to treatment failure. To investigate HR in Enterococcus faecalis, we performed population analysis profiling (PAP) on 40 clinical isolates against five clinically important antibiotics and whole-genome sequenced (WGS) the resistant subpopulations. HR was identified for daptomycin (20.0%), gentamicin (13.2%), and tigecycline (35.9%), but not for linezolid, and vancomycin. Genomic analysis revealed that daptomycin resistance was primarily caused by mutations affecting cell envelope integrity and stress-response pathways. Gentamicin resistance was linked to alterations in efflux regulation, ribosomal proteins synthesis, and transcriptional control. Tigecycline resistance involved deletions in the tet(M) leader peptide, resulting in a 25-fold increased tet(M) expression, as well as transposition of the transposon Tn916 carrying tet(M) to multiple chromosomal sites, causing an increased gene dosage of tet(M). These findings highlight the role of chromosomal mutations and mobile genetic elements in causing HR in E. faecalis Author SummaryAntibiotic resistance is one of the most critical challenges in modern medicine, undermining the efficacy of antimicrobial therapies and compromising patient safety. Bacterial strains that are heteroresistant (HR), show a minor subpopulation of resistant bacteria within a main susceptible bacterial population. HR strains are mostly classified as susceptible strains since the subpopulation are usually too small to be detected with standard susceptibility testing. Treatment with antibiotics will lead to survival and increase of the resistant subpopulation that can lead to treatment failure. In this study, we observed a high frequency of HR among clinical Enterococcus faecalis strains against gentamicin, daptomycin and tigecycline, three commonly used antibiotics for treatment of E. faecalis infections. Chromosomal mutations and changes in gene expression were the genetic mechanisms generating the resistant subpopulations.

microbiology↗

bioRxiv2025

Sulbactam-durlobactam susceptibility among cefiderocol heteroresistant Acinetobacter

The ATTACK clinical trial for treatment of carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) isolates determined treatment with sulbactam-durlobactam to be efficacious and safe. However, other newly introduced {beta}-lactam antibiotics, including the novel cephalosporin cefiderocol, have been compromised upon clinical introduction by a type of antibiotic resistance called heteroresistance, in which only a small subpopulation of total cells exhibit phenotypic resistance. Therefore, we sought to test for sulbactam-durlobactam heteroresistance, as well as whether sulbactam-durlobactam was effective against cefiderocol heteroresistant CRAB isolates. We did not observe heteroresistance (or conventional resistance) to sulbactam-durlobactam among the 107 carbapenem-resistant Acinetobacter isolates tested, consistent with the efficacy of this new antibiotic in the ATTACK trial. Further, sulbactam-durlobactam was active against cefiderocol heteroresistant CRAB, highlighting that this antibiotic may be prioritized in relation to cefiderocol in treating CRAB infections.

microbiology↗

bioRxiv2022

Heteroresistance via beta-lactamase gene amplification threatens the beta-lactam pipeline

It is unclear how bacteria rapidly adapt to resist novel drugs upon their introduction. Heteroresistance (HR) is a form of antibiotic resistance where a phenotypically unstable minority resistant subpopulation co-exists with a susceptible population. We observed HR to cefiderocol, a novel beta-lactam developed to resist beta-lactamases including extended-spectrum-beta-lactamases (ESBLs), among clinical isolates collected before its use. The resistant subpopulation in Enterobacter was a continuum; increasing gene copy number of an otherwise ineffective ESBL mediated increased resistance in decreasing numbers of cells. The factors that control the magnitude of amplification are unclear. We observed that ESBL activity controlled the level of amplification, thus increased copy number can compensate for poor enzymatic activity. A Klebsiella isolate from a clinical treatment failure also demonstrated amplification, highlighting the relevance of this phenomenon. These data provide insights into factors controlling dynamics of HR and how bacteria use phenotypic resistance to flexibly confront new antibiotic threats.

microbiology↗