Molecular detection of glpT and uhpT genes as fosfomycin pathways in UTI infection patients

Garallah, Eman Thamer; Al-Jubori, Sawsan Sajid

doi:10.1016/j.genrep.2020.100930

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…According to Garallah and Al-Jubori from Iraq, mutations in the glpT and uhpT genes act as efflux pumps and exclude fosfomycin from bacterial cells, leading to fosfomycin resistance in E. coli isolates from UTIs in their region (28). In the Bahy et al study, similar to ours, there was no resistance to fosfomycin via plasmidic fos A and fos C2.…”

Section: Discussionsupporting

confidence: 79%

Molecular Analysis of Fosfomycin Resistance Among Escherichia coli Isolates from Urinary Tract Infections in Kidney Transplant Patients During 2019 - 2020

Najafikhah,

Hakemi-Vala,

Samavat

et al. 2023

Arch Clin Infect Dis

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Background: This study aimed to estimate the prevalence of fosfomycin resistance and the frequency of extended-spectrum beta-lactamase (ESBL) production in Escherichia coli isolates from three kidney transplant patients (KTPs) in Tehran. Methods: Sixty clinical isolates of uropathogenic E. coli were collected from three kidney transplant centers in Tehran between April and May 2019. Antimicrobial susceptibility testing (AST), minimum inhibitory concentration (MIC) of fosfomycin, and screening for ESBL production were conducted following the protocols established by the Clinical and Laboratory Standards Institute (CLSI). The presence of the blaTEM, blaSHV, blaCTX-M, fosA3, and fosC2 genes was evaluated using polymerase chain reaction (PCR) and sequencing. Additionally, mutations in the murA, glpT, uhpT, and cya genes were assessed. The activity of the carbohydrate phosphate transporter was measured using the real-time PCR assay. Results: According to the AST results, ampicillin showed the highest resistance rate (86%), while ertapenem and doripenem exhibited complete susceptibility (100%). According to the E-test, 1.6% of E. coli isolates were resistant to fosfomycin. Furthermore, 33.4% of E. coli isolates in KTPs were ESBL producers, with the most frequent occurrence of the blaTEM gene (55%). Additionally, mutations were identified in the murA, uhpT, and glpT genes of resistant samples. No plasmid genes for fosA3 and fosC2 were detected. The expression of the uhpT gene increased 32-fold in a susceptible isolate, as determined by qPCR. Conclusions: The high resistance of E. coli isolates from urinary tract infections (UTIs) of KTPs to β-lactam antibiotics remains a significant clinical challenge. However, no correlation was found between ESBL production and resistance to fosfomycin. The resistance rate to fosfomycin was low, and the primary cause of resistance was mutations in chromosomal genes.

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Section: Discussionsupporting

confidence: 79%

Molecular Analysis of Fosfomycin Resistance Among Escherichia coli Isolates from Urinary Tract Infections in Kidney Transplant Patients During 2019 - 2020

Najafikhah,

Hakemi-Vala,

Samavat

et al. 2023

Arch Clin Infect Dis

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“…Previous studies correlated the increased Fos R in NICs to mutations within the glpT transporter gene, as well as components of the UhpBA two-component system and its regulon, which affect fosfomycin import into the cell [11], [14], [16]. Indeed, deletion of the two-component system uhpBA that positively regulates uhpT in cystitis isolate UTI89 renders the resulting strain fosfomycin resistant (Fig.…”

Section: Loss Of Uhp Genes -The Most Common Route To Fos R -Is Not As...mentioning

confidence: 86%

“…Fosfomycin enters the bacterial cell through at least two sugar transporters, UhpT (Fig. 1A) and GlpT, which transport glucose-6-phosphate (G6P) and glycerol-3-phosphate (G3P) respectively [11]. This is believed to be due to structural similarities between fosfomycin and their cognate targets (Fig 1C).…”

Section: Introductionmentioning

confidence: 99%

Drug Resistance without a cost? Common and uncommon routes to fosfomycin resistance in UropathogenicEscherichia coli

Bermudez,

Brannon,

Dudipala

et al. 2023

Preprint

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Fosfomycin kills bacteria by blocking the binding of phosphoenolpyruvate (PEP) to the bacterial enzyme MurA and halting peptidoglycan synthesis. While its use has increased with the emergence of antibiotic resistance, the mechanisms leading to fosfomycin resistance remain relatively unexplored. In uropathogenicEscherichia coli(UPEC) that accounts for >75% of urinary tract infections (UTIs), fosfomycin enters the cell primarily through UhpT, which transports glucose-6-phosphate (G6P) glycolysis intermediate into the cell. Mutations inuhpT lead to fosfomycin resistance and have been identified during antimicrobial susceptibility testing (AST) in non-susceptible inner colonies that form within the zone of inhibition. However, EUCAST and CLSI guidelines differ in how to read fosfomycin AST when such resistant colonies arise. Work from our lab and others demonstrated that glycolysis is dispensable during acute UTI. Moreover, G6P is scarce in urine, prompting us to test the hypothesis thatuhpmutations may not impart a fitness cost to the pathogen. We report that loss ofuhpindeed does not impair UPEC pathogenesis and that clinical isolates exist that lack theuhplocus altogether. Analysis of non-susceptible inner colonies revealed a suite of novel genes involved in fosfomycin resistance. One of them is PykF that converts PEP to pyruvate during glycolysis. Single deletions ofpykFor its anaerobic homologpykAdo not attenuate UPEC. Based on our data, we raise the alarm that multiple routes lead to fosfomycin resistance and do not affect pathogenesis and propose that the current EUCAST and CLSI guidelines unify into how they evaluate fosfomycin AST.

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“…The UhpT and GlpT transporters facilitate fosfomycin incorporation into bacterial cells ( Silver, 2017 ). The reduced expression or introduction of glpT or uhpT mutations and the efflux pump can decrease fosfomycin uptake and thus lower antibiotic susceptibility ( Garallah and Al-Jubori, 2020 ). Several studies have now shown that the overuse of antibiotics in the food chain and the presence of several antibiotic resistance operons promote multiresistance to these drugs ( Ferri et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Cronobacter spp. and Salmonella spp. Strains Isolated From Powdered Infant Formula in Chile

et al. 2022

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This study characterized five Cronobacter spp. and six Salmonella spp. strains that had been isolated from 155 samples of powdered infant formula (PIF) sold in Chile and manufactured in Chile and Mexico in 2018–2020. Two strains of Cronobacter sakazakii sequence type (ST) ST1 and ST31 (serotypes O:1 and O:2) and one strain of Cronobacter malonaticus ST60 (O:1) were identified. All Salmonella strains were identified as Salmonella Typhimurium ST19 (serotype O:4) by average nucleotide identity, ribosomal multilocus sequence typing (rMLST), and core genome MLST (cgMLST). The C. sakazakii and C. malonaticus isolates were resistant to cephalothin, whereas the Salmonella isolates were resistant to oxacillin and ampicillin. Nineteen antibiotic resistance genes were detected in the C. sakazakii and C. malonaticus isolates; the most prevalent were mcr-9.1, blaCSA, and blaCMA. In Salmonella, 30 genes encoding for aminoglycoside and cephalosporin resistance were identified, including aac(6′)-Iaa, β-lactamases ampH, ampC1, and marA. In the Cronobacter isolates, 32 virulence-associated genes were detected by WGS and clustered as flagellar proteins, outer membrane proteins, chemotaxis, hemolysins, invasion, plasminogen activator, colonization, transcriptional regulator, survival in macrophages, use of sialic acid, and toxin-antitoxin genes. In the Salmonella strains, 120 virulence associated genes were detected, adherence, magnesium uptake, resistance to antimicrobial peptides, secretion system, stress protein, toxin, resistance to complement killing, and eight pathogenicity islands. The C. sakazakii and C. malonaticus strains harbored I-E and I-F CRISPR-Cas systems and carried Col(pHHAD28) and IncFIB(pCTU1) plasmids, respectively. The Salmonella strains harbored type I-E CRISPR-Cas systems and carried IncFII(S) plasmids. The presence of C. sakazakii and Salmonella in PIF is a health risk for infants aged less than 6 months. For this reason, sanitary practices should be reinforced for its production and retail surveillance.

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Molecular detection of glpT and uhpT genes as fosfomycin pathways in UTI infection patients

Cited by 6 publications

References 19 publications

Molecular Analysis of Fosfomycin Resistance Among Escherichia coli Isolates from Urinary Tract Infections in Kidney Transplant Patients During 2019 - 2020

Molecular Analysis of Fosfomycin Resistance Among Escherichia coli Isolates from Urinary Tract Infections in Kidney Transplant Patients During 2019 - 2020

Drug Resistance without a cost? Common and uncommon routes to fosfomycin resistance in UropathogenicEscherichia coli

Genomic Characterization of Cronobacter spp. and Salmonella spp. Strains Isolated From Powdered Infant Formula in Chile

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