The molecular basis of extensively drug-resistant Salmonella Typhi isolates from pediatric septicemia patients

Kim, Chanmi; Latif, Iqra; Neupane, Durga; Lee, Gi Young; Kwon, Ryan S.; Batool, Aisha; Ahmed, Qasim; Qamar, Muhammad Usman; Song, Jeongmin

doi:10.1371/journal.pone.0257744

Cited by 9 publications

(17 citation statements)

References 45 publications

(52 reference statements)

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“…This observation supports the idea that neutralizing VHH antibodies identified from this study can neutralize typhoid toxin produced by S. Typhi clinical isolates. Like other bacterial pathogens with public health relevance, multidrug-resistant (MDR) and extensively drug-resistant (XDR) S. Typhi is widespread globally ( 26 – 30 ). We recently formally demonstrated that typhoid toxin is continuously secreted by antibiotic-resistant S. Typhi even when S. Typhi-infected host cells are treated with antibiotics ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

et al. 2022

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Typhoid toxin is secreted by the typhoid fever-causing bacterial pathogen Salmonella Typhi and has tropism for immune cells and brain endothelial cells. Here, we generated a camelid single domain antibody (VHH) library from typhoid toxoid-immunized alpacas and identified 41 VHHs selected on the glycan-receptor binding PltB and nuclease CdtB. VHHs exhibiting potent in vitro neutralizing activities from each sequence-based family were epitope binned via competition ELISAs, leading to 6 distinct VHHs, two anti-PltB (T2E7 and T2G9) and four anti-CdtB VHHs (T4C4, T4C12, T4E5, and T4E8), whose in vivo neutralizing activities and associated toxin neutralizing mechanisms were investigated. We found that T2E7, T2G9, and T4E5 effectively neutralized typhoid toxin in vivo , as demonstrated by 100% survival of mice administered a lethal-dose of typhoid toxin and with little to no typhoid toxin-mediated upper motor function defect. Cumulatively, these results highlight the potential of the compact antibodies to neutralize typhoid toxin by targeting the glycan-binding and/or nuclease subunits.

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Section: Discussionmentioning

confidence: 99%

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

et al. 2022

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“…Genetic elements identifying the mobile gene cassettes that carry multidrug-resistant genes are known as integrons. In S. Typhi , the presence of integrons (class 1 and 2) equalizes the distribution of antimicrobial resistance, in which class 1 is more dominantly found [ 96 , 97 , 98 ].…”

Section: Mechanisms Of Antimicrobial Resistance In S Typhimentioning

confidence: 99%

Understanding the Mechanism of Antimicrobial Resistance and Pathogenesis of Salmonella enterica Serovar Typhi

Khan

Shamim

2022

Microorganisms

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Salmonella enterica serovar Typhi (S. Typhi) is a Gram-negative pathogen that causes typhoid fever in humans. Though many serotypes of Salmonella spp. are capable of causing disease in both humans and animals alike, S. Typhi and S. Paratyphi are common in human hosts only. The global burden of typhoid fever is attributable to more than 27 million cases each year and approximately 200,000 deaths worldwide, with many regions such as Africa, South and Southeast Asia being the most affected in the world. The pathogen is able to cause disease in hosts by evading defense systems, adhesion to epithelial cells, and survival in host cells in the presence of several virulence factors, mediated by virulence plasmids and genes clustered in distinct regions known as Salmonella pathogenicity islands (SPIs). These factors, coupled with plasmid-mediated antimicrobial resistance genes, enable the bacterium to become resistant to various broad-spectrum antibiotics used in the treatment of typhoid fever and other infections caused by Salmonella spp. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains in many countries of the world has raised great concern over the rise of antibiotic resistance in pathogens such as S. Typhi. In order to identify the key virulence factors involved in S. Typhi pathogenesis and infection, this review delves into various mechanisms of virulence, pathogenicity, and antimicrobial resistance to reinforce efficacious disease management.

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“…Typhi pathogens frequently carry the plasmid-mediated bla TEM-1 , dhfR7, sul1, and catA1 genes and extensively drug-resistant (XDR) S . Typhi carry parE and bla CTX-M-15 antimicrobial resistance genes (ARGs) [ 11 ]. A recent Pakistani study revealed the spread of MDR (50.1%) and XDR (33%) S .…”

Section: Introductionmentioning

confidence: 99%

Antibacterial efficacy of indigenous Pakistani honey against extensively drug-resistant clinical isolates of Salmonella enterica serovar Typhi: an alternative option to combat antimicrobial resistance

Ejaz

Sultan

Qamar

et al. 2023

BMC Complement Med Ther

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Background Extensively drug-resistant (XDR) Salmonella enterica serovar Typhi (S. Typhi) poses a grave threat to public health due to increased mortality and morbidity caused by typhoid fever. Honey is a promising antibacterial agent, and we aimed to determine the antibacterial activity of honey against XDR S. Typhi. Methods We isolated 20 clinical isolates of XDR S. Typhi from pediatric septicemic patients and determined the minimum inhibitory concentrations (MICs) of different antibiotics against the pathogens using the VITEK 2 Compact system. Antimicrobial-resistant genes carried by the isolates were identified using PCR. The antibacterial efficacy of five Pakistani honeys was examined using agar well diffusion assay, and their MICs and minimum bactericidal concentrations (MBCs) were determined with the broth microdilution method. Results All 20 isolates were confirmed as S. Typhi. The antibiogram phenotype was confirmed as XDR S. Typhi with resistance to ampicillin (≥ 32 µg/mL), ciprofloxacin (≥ 4 µg/mL), and ceftriaxone (≥ 4 µg/mL) and sensitivity to azithromycin (≤ 16 µg/mL) and carbapenems (≤ 1 µg/mL). Molecular conformation revealed the presence of blaTM-1, Sul1, qnrS, gyrA, gyrB, and blaCTX-M-15 genes in all isolates. Among the five honeys, beri honey had the highest zone of inhibition of 7–15 mm and neem honey had a zone of inhibition of 7–12 mm. The MIC and MBC of beri honey against 3/20 (15%) XDR S. Typhi isolates were 3.125 and 6.25%, respectively, while the MIC and MBC of neem were 3.125 and 6.25%, respectively, against 3/20 (15%) isolates and 6.25 and 12.5%, respectively, against 7/20 (35%) isolates. Conclusion Indigenous honeys have an effective role in combating XDR S. Typhi. They are potential candidates for clinical trials as alternative therapeutic options against XDR S. Typhi isolates.

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The molecular basis of extensively drug-resistant Salmonella Typhi isolates from pediatric septicemia patients

Cited by 9 publications

References 45 publications

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

Neutralization of Typhoid Toxin by Alpaca-Derived, Single-Domain Antibodies Targeting the PltB and CdtB Subunits

Understanding the Mechanism of Antimicrobial Resistance and Pathogenesis of Salmonella enterica Serovar Typhi

Antibacterial efficacy of indigenous Pakistani honey against extensively drug-resistant clinical isolates of Salmonella enterica serovar Typhi: an alternative option to combat antimicrobial resistance

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