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1.
BMC Infect Dis ; 24(1): 727, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39048963

ABSTRACT

BACKGROUND: Understanding the source of typhoid infections and the genetic relatedness of Salmonella Typhi (S. Typhi) by cluster identification in endemic settings is critical for establishing coordinated public health responses for typhoid fever management. This study investigated the genotypic diversity, antibiotic resistance mechanisms, and clustering of 35 S.Typhi strains isolated from cases and carriers in the Mukuru Informal Settlement. METHODS: We studied 35 S.Typhi isolates, including 32 from cases and 3 from carriers, from study participants in the informal settlement of Mukuru, Nairobi, Kenya. Genomic DNA was extracted, and whole-genome sequencing (WGS) was performed to determine the phylogenetic relatedness of strains and detect antimicrobial resistance determinants (AMR). WGS data were analyzed using bioinformatics tools available at the Center for Genomic Epidemiology and Pathogenwatch platforms. RESULTS: Genotype 4.3.1.2 EA3 was found to be dominant at 46% (16/35), followed by 4.3.1.2 EA2 at 28% (10/35), and 4.3.1.1 EA1 at 27% (9/35). A comparison of the isolates with global strains from Pathogenwatch identified close clustering with strains from Uganda, Tanzania, Rwanda, and India. Three isolates (9%) distributed in each cluster were isolated from carriers. All genotype 4.3.1.2 EA3 isolates were genotypically multidrug-resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. Single mutations in the quinolone resistance-determining region were identified in the gyrA (S83Y) and gyrB (S464F) genes. All isolates associated with multidrug resistance showed the presence of the IncQ1 plasmid with the following genes: blaTEM-1B, catA1, sul1, sul2, and dfrA7. CONCLUSION: The close phylogenetic relatedness between antimicrobial-resistant case isolates and carriage isolates indicates that typhoid carriage is a possible source of infection in the community. Comparative analysis with global isolates revealed that the Kenyan isolates share common lineages with strains from neighboring East African countries and India, suggesting regional dissemination of specific MDR clones. AMR was a major feature of the isolates. Surveillance and testing for antimicrobial susceptibility should inform options for the management of cases.


Subject(s)
Anti-Bacterial Agents , Genetic Variation , Genotype , Phylogeny , Salmonella typhi , Typhoid Fever , Whole Genome Sequencing , Kenya/epidemiology , Salmonella typhi/genetics , Salmonella typhi/drug effects , Salmonella typhi/classification , Salmonella typhi/isolation & purification , Humans , Typhoid Fever/microbiology , Typhoid Fever/epidemiology , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity Tests , Male , Adult , Adolescent , Child , Female , Child, Preschool , Drug Resistance, Bacterial/genetics , Young Adult
2.
Molecules ; 29(13)2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38998957

ABSTRACT

A new class of thiophene-based molecules of 5-bromothiophene-2-carboxylic acid (1) have been synthesized in current research work. All analogs 4A-4G were synthesized with optimized conditions by coupling reactions of 2-ethylhexyl 5-bromothiophene-2-carboxylate (3) with various arylboronic acids. The results indicated that the majority of compounds showed promising effective in vitro antibacterial activity. Herein, 2-ethylhexyl-5-(p-tolyl)thiophene-2-carboxylate (4F), in particular among the synthesized analogs, showed outstanding antibacterial action (MIC value 3.125 mg/mL) against XDR Salmonella Typhi compared to ciprofloxacin and ceftriaxone. The intermolecular interaction was investigated by using a molecular docking study of thiophene derivatives 4A-4G against XDR S. Typhi. The values of the binding affinity of functionalized thiophene molecules and ciprofloxacin were compared against bacterial enzyme PDB ID: 5ztj. Therefore, 4F appears to be a promising antibacterial agent and showed the highest potential value. Density functional theory (DFT) calculations were executed to examine the electronic, structural, and spectroscopic features of the newly synthesized molecules 4A-4G.


Subject(s)
Anti-Bacterial Agents , Microbial Sensitivity Tests , Molecular Docking Simulation , Salmonella typhi , Thiophenes , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Salmonella typhi/drug effects , Thiophenes/chemistry , Thiophenes/pharmacology , Thiophenes/chemical synthesis , Density Functional Theory , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Molecular Structure , Structure-Activity Relationship , Ciprofloxacin/pharmacology , Ciprofloxacin/chemistry
3.
Ghana Med J ; 58(1): 86-90, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38957275

ABSTRACT

Objective: This study aims to examine the frequency of Salmonella Paratyphi found in blood cultures and evaluate the antibiotic susceptibility pattern of Salmonella isolates to different antibiotics. Additionally, the study aims to assess the paradigm shift in the trend of enteric fever caused by Salmonella Typhi (S. Typhi) to Salmonella Paratyphi(S. Paratyphi) . Study Design: Retrospective study. Participant: The study enrolled patients aged 12 years and above diagnosed with enteric fever (positive blood culture) and admitted to Peelamedu Samanaidu Govindasamy Naidu (PSG) Hospital. Interventions: The study analyzed demographic and antibiotic susceptibility profiles of Salmonella isolates collected from 106 enteric fever patients in the hospital between 2010 and 2022. The susceptibility profiles of Salmonella isolates to multiple antibiotics were assessed. Results: There were 106 participants, and 95 (89.62%) of them had enteric fever linked to Salmonella Typhi, while only 11 (10.38%) had enteric fever linked to Salmonella Paratyphi A. From 2010 to 2022, the study discovered a general decline in the prevalence of enteric fever caused by Salmonella species. But between 2014 and 2022, the incidence of enteric fever linked to S. Typhi rapidly increased. Azithromycin (100% , n = 106) and ceftriaxone (99% , n = 105) were highly effective against the Salmonella isolates, whereas nalidixic acid was resisted by 3 isolates (4.72%, n = 3). Conclusion: The study observed a higher incidence of Salmonella Typhi in comparison to Paratyphi A and a greater susceptibility of males to enteric fever. Funding: None declared.


Subject(s)
Anti-Bacterial Agents , Microbial Sensitivity Tests , Salmonella paratyphi A , Salmonella typhi , Typhoid Fever , Humans , Male , Female , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Typhoid Fever/epidemiology , Typhoid Fever/microbiology , Typhoid Fever/drug therapy , Retrospective Studies , Salmonella typhi/drug effects , Salmonella typhi/isolation & purification , Salmonella paratyphi A/drug effects , Salmonella paratyphi A/isolation & purification , Adult , Adolescent , Child , Middle Aged , Young Adult , Paratyphoid Fever/epidemiology , Paratyphoid Fever/microbiology , Paratyphoid Fever/drug therapy , Incidence , Drug Resistance, Bacterial , Azithromycin/therapeutic use , Azithromycin/pharmacology , Ceftriaxone/therapeutic use , Ceftriaxone/pharmacology , Aged , Prevalence
5.
PLoS One ; 19(6): e0303285, 2024.
Article in English | MEDLINE | ID: mdl-38917154

ABSTRACT

Typhoid fever, caused by Salmonella enterica serovar typhi, presents a substantial global health threat, particularly in regions with limited healthcare infrastructure. The rise of multidrug-resistant strains of S. typhi exacerbates this challenge, severely compromising conventional treatment efficacy due to over activity of efflux pumps. In our study, a comprehensive exploration of two fundamental aspects to combat MDR in S. typhi is carried out; i.e. employing advanced bioinformatics analyses and AlphaFold AI, We successfully identified and characterised a putative homologue, ABC-TPA, reminiscent of the P-glycoprotein (P-gp) known for its role in multidrug resistance in diverse pathogens. This discovery provides a critical foundation for understanding the potential mechanisms driving antibiotic resistance in S. typhi. Furthermore, employing computational methodologies, We meticulously assessed the potential of lignans, specifically Schisandrin A, B, and C, as promising Efflux Pump Inhibitors (EPIs) against the identified P-gp homologue in S. typhi. Noteworthy findings revealed robust binding interactions of Schisandrin A and B with the target protein, indicating substantial inhibitory capabilities. In contrast, Schisandrin C exhibited instability, showing varied effectiveness among the evaluated lignans. Pharmacokinetics and toxicity predictions underscored the favourable attributes of Schisandrin A, including prolonged action duration. Furthermore, high systemic stability and demanished toxicity profile of SA and SB present their therapeutic efficacy against MDR. This comprehensive investigation not only elucidates potential therapeutic strategies against MDR strains of S. typhi but also highlights the relevance of computational approaches in identifying and evaluating promising candidates. These findings lay a robust foundation for future empirical studies to address the formidable challenges antibiotic resistance poses in this clinically significant infectious diseases.


Subject(s)
Anti-Bacterial Agents , Drug Resistance, Multiple, Bacterial , Lignans , Salmonella typhi , Salmonella typhi/drug effects , Drug Resistance, Multiple, Bacterial/drug effects , Lignans/pharmacology , Lignans/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Bacterial Proteins/metabolism , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/genetics , Humans , Microbial Sensitivity Tests , Computational Biology/methods
6.
Commun Biol ; 7(1): 775, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38942806

ABSTRACT

Antimicrobial resistance (AMR) poses a serious threat to the clinical management of typhoid fever. AMR in Salmonella Typhi (S. Typhi) is commonly associated with the H58 lineage, a lineage that arose comparatively recently before becoming globally disseminated. To better understand when and how H58 emerged and became dominant, we performed detailed phylogenetic analyses on contemporary genome sequences from S. Typhi isolated in the period spanning the emergence. Our dataset, which contains the earliest described H58 S. Typhi organism, indicates that ancestral H58 organisms were already multi-drug resistant (MDR). These organisms emerged spontaneously in India in 1987 and became radially distributed throughout South Asia and then globally in the ensuing years. These early organisms were associated with a single long branch, possessing mutations associated with increased bile tolerance, suggesting that the first H58 organism was generated during chronic carriage. The subsequent use of fluoroquinolones led to several independent mutations in gyrA. The ability of H58 to acquire and maintain AMR genes continues to pose a threat, as extensively drug-resistant (XDR; MDR plus resistance to ciprofloxacin and third generation cephalosporins) variants, have emerged recently in this lineage. Understanding where and how H58 S. Typhi originated and became successful is key to understand how AMR drives successful lineages of bacterial pathogens. Additionally, these data can inform optimal targeting of typhoid conjugate vaccines (TCVs) for reducing the potential for emergence and the impact of new drug-resistant variants. Emphasis should also be placed upon the prospective identification and treatment of chronic carriers to prevent the emergence of new drug resistant variants with the ability to spread efficiently.


Subject(s)
Anti-Bacterial Agents , Phylogeny , Salmonella typhi , Typhoid Fever , Salmonella typhi/genetics , Salmonella typhi/drug effects , Typhoid Fever/microbiology , Typhoid Fever/drug therapy , Typhoid Fever/epidemiology , Humans , Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Haplotypes , Mutation , Genome, Bacterial
7.
J Pediatric Infect Dis Soc ; 13(6): 337-339, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38717105

ABSTRACT

Extensively drug-resistant (XDR) strains of Salmonella enterica serotype Typhi have emerged in Pakistan and Iraq. We report 13 children with enteric fever in Southeast Texas seen over 3.5 years, of whom 23.1% had XDR isolates.


Subject(s)
Salmonella typhi , Typhoid Fever , Humans , Texas/epidemiology , Typhoid Fever/epidemiology , Typhoid Fever/drug therapy , Typhoid Fever/microbiology , Child, Preschool , Child , Male , Female , Salmonella typhi/drug effects , Salmonella typhi/isolation & purification , Anti-Bacterial Agents/therapeutic use , Infant , Drug Resistance, Multiple, Bacterial , Adolescent
8.
ACS Infect Dis ; 10(6): 1990-2001, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38815059

ABSTRACT

Conserved molecular signatures in multidrug-resistant Salmonella typhi can serve as novel therapeutic targets for mitigation of infection. In this regard, we present the S. typhi cell division activator protein (StCAP) as a conserved target across S. typhi variants. From in silico and fluorimetric assessments, we found that StCAP is a DNA-binding protein. Replacement of the identified DNA-interacting residue Arg34 of StCAP with Ala34 showed a dramatic (15-fold) increase in Kd value compared to the wild type (Kd 546 nm) as well as a decrease in thermal stability (10 °C shift). Out of the two screened molecules against the DNA-binding pocket of StCAP, eltrombopag, and nilotinib, the former displayed better binding. Eltrombopag inhibited the stand-alone S. typhi culture with an IC50 of 38 µM. The effect was much more pronounced on THP-1-derived macrophages (T1Mac) infected with S. typhi where colony formation was severely hindered with IC50 reduced further to 10 µM. Apoptotic protease activating factor1 (Apaf1), a key molecule for intrinsic apoptosis, was identified as an StCAP-interacting partner by pull-down assay against T1Mac. Further, StCAP-transfected T1Mac showed a significant increase in LC3 II (autophagy marker) expression and downregulation of caspase 3 protein. From these experiments, we conclude that StCAP provides a crucial survival advantage to S. typhi during infection, thereby making it a potent alternative therapeutic target.


Subject(s)
Bacterial Proteins , Salmonella typhi , Salmonella typhi/drug effects , Salmonella typhi/genetics , Salmonella typhi/pathogenicity , Humans , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Apoptosis/drug effects , Macrophages/microbiology , Macrophages/drug effects , THP-1 Cells , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Autophagy/drug effects , Typhoid Fever/microbiology , Cell Division/drug effects
9.
Microb Pathog ; 191: 106676, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38710290

ABSTRACT

Enteric fever, a persistent public health challenge in developing regions, is exacerbated by suboptimal socioeconomic conditions, contaminated water and food sources, and insufficient sanitation. This study delves into the antimicrobial susceptibility of Salmonella Typhi, uncovering the genetic underpinnings of its resistance. Analyzing 897 suspected cases, we identified a significant prevalence of typhoid fever, predominantly in males (58.3 %) and younger demographics. Alarmingly, our data reveals an escalation in resistance to both primary and secondary antibiotics, with cases of multi-drug resistant (MDR) and extensively drug-resistant (XDR) S. Typhi reaching 14.7 % and 43.4 %, respectively, in 2021. The Multiple Antibiotic Resistance (MAR) index exceeded 0.2 in over half of the isolates, signaling widespread antibiotic misuse. The study discerned 47 unique antibiotic resistance patterns and pinpointed carbapenem and macrolide antibiotics as the remaining effective treatments against XDR strains, underlining the critical need to preserve these drugs for severe cases. Molecular examinations identified blaTEM, blaSHV, and blaCTX-M genes in ceftriaxone-resistant strains, while qnrS was specific to ciprofloxacin-resistant variants. Notably, all examined strains exhibited a singular mutation in the gyrA gene, maintaining wild-type gyrB and parC genes. The erm(B) gene emerged as the primary determinant of azithromycin resistance. Furthermore, a distressing increase in resistance genes was observed over three years, with erm(B), blaTEM and qnrS showing significant upward trends. These findings are a clarion call for robust antimicrobial stewardship programs to curtail inappropriate antibiotic use and forestall the burgeoning threat of antibiotic resistance in S. Typhi.


Subject(s)
Anti-Bacterial Agents , Drug Resistance, Multiple, Bacterial , Microbial Sensitivity Tests , Salmonella typhi , Typhoid Fever , Typhoid Fever/microbiology , Typhoid Fever/epidemiology , Salmonella typhi/drug effects , Salmonella typhi/genetics , Humans , Anti-Bacterial Agents/pharmacology , Male , Female , Drug Resistance, Multiple, Bacterial/genetics , Adult , Child, Preschool , Adolescent , Child , Young Adult , Middle Aged , Infant , Prevalence , Aged , Drug Resistance, Bacterial/genetics , Mutation , Bacterial Proteins/genetics
10.
J Infect Dev Ctries ; 18(4): 550-555, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38728649

ABSTRACT

INTRODUCTION: Pakistan has been experiencing an extensively drug-resistant (XDR) outbreak of typhoid for some years. We sought to evaluate how the COVID-19 pandemic impacted typhoid epidemiology in Pakistan, from the beginning of the pandemic in 2020 through the end of 2022, and the reduction of COVID-19 cases. METHODOLOGY: We compared national public COVID-19 data with retrospectively obtained patient data of confirmed S. Typhi isolates between January 2019 and December 2022 from Shaukat Khanum Memorial Cancer Hospital and Research Centre and the hospital's extended network of laboratory collection centers across Pakistan. RESULTS: We observed that during the early onset of the COVID-19 pandemic and COVID-19 peaks, typhoid positivity generally decreased. This suggests that restrictions and non-pharmaceutical interventions that limited social interactions and promoted good sanitation and hygiene practices had a positive secondary effect on typhoid. This led to an overall yearly decrease in typhoid positivity between 2019 to 2021. However, the percentage of S. Typhi cases isolated that were ceftriaxone-resistant continued to increase, suggesting the continued dominance of XDR typhoid in Pakistan. In 2022, with the alleviation of pandemic restrictions, we observed increased typhoid positivity and COVID-19 and typhoid positivity started to follow similar trends. CONCLUSIONS: Given the continued presence of COVID-19 along with XDR typhoid in Pakistan, it will be imperative to use differential testing to ensure that the epidemiology of each reported is accurate, the spread of each it contained, and that antibiotics are not misused. The use of approved vaccinations will lessen the burden of both diseases.


Subject(s)
COVID-19 , Salmonella typhi , Typhoid Fever , Typhoid Fever/epidemiology , Pakistan/epidemiology , Humans , COVID-19/epidemiology , COVID-19/prevention & control , Salmonella typhi/drug effects , Salmonella typhi/isolation & purification , Retrospective Studies , SARS-CoV-2 , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology
11.
Diagn Microbiol Infect Dis ; 109(4): 116354, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38776664

ABSTRACT

The study was done to assess the antimicrobial susceptibility pattern among Salmonella enterica serovars causing bacteremia in Northern India. In this observational study, blood samples positive for Salmonella enterica serovars from January 2021 to April 2023 were studied. Species identification was done using MALDI-ToF MS. Serotyping was done using slide agglutination method. Antimicrobial susceptibility was interpreted as per the CLSI guidelines. During the study period, 32 Salmonella enterica serovars were isolated. Salmonella enterica serovar Typhi was the predominant serovar, followed by Salmonella enterica serovar Paratyphi A. All isolates were susceptible to ceftriaxone, chloramphenicol, co-trimoxazole and cefotaxime. Pefloxacin showed 100% resistance. Resistance to nalidixic acid was found in 81.2% isolates. Of the isolates resistant to nalidixic acid, 19(73.08%) isolates were resistant to ciprofloxacin also. This changing susceptibility pattern necessitates continuous surveillance of antibiogram of Salmonella isolates to rationalize the treatment protocols for invasive salmonellosis and prevent emergence of resistant strains.


Subject(s)
Anti-Bacterial Agents , Bacteremia , Microbial Sensitivity Tests , Salmonella Infections , Tertiary Care Centers , Humans , Bacteremia/microbiology , Bacteremia/epidemiology , India/epidemiology , Tertiary Care Centers/statistics & numerical data , Anti-Bacterial Agents/pharmacology , Salmonella Infections/microbiology , Salmonella Infections/epidemiology , Serogroup , Salmonella enterica/drug effects , Salmonella enterica/isolation & purification , Salmonella/drug effects , Salmonella/isolation & purification , Salmonella/classification , Adult , Male , Drug Resistance, Bacterial , Serotyping , Middle Aged , Young Adult , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Female , Salmonella typhi/drug effects , Salmonella typhi/isolation & purification
12.
Diagn Microbiol Infect Dis ; 109(3): 116276, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38613950

ABSTRACT

Salmonella enterica serotype Typhi (S Typhi) associated urinary tract infections are exceedingly rare, accounting for less than 1% of cases. Such infections have known to occur in immune-compromised or individuals with urogenital structural abnormalities. With the emergence of extensively drug resistant S Typhi strains in Pakistan, the management of its various unique presentations poses therapeutic challenges. We report the first documented case of a 74 years old male patient presenting with relapsed urinary tract infection secondary to extensively drug resistant S Typhi.


Subject(s)
Anti-Bacterial Agents , Drug Resistance, Multiple, Bacterial , Recurrence , Salmonella typhi , Typhoid Fever , Urinary Tract Infections , Humans , Male , Salmonella typhi/drug effects , Salmonella typhi/isolation & purification , Urinary Tract Infections/microbiology , Urinary Tract Infections/drug therapy , Typhoid Fever/microbiology , Typhoid Fever/drug therapy , Aged , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/pharmacology , Pakistan , Microbial Sensitivity Tests
14.
J Paediatr Child Health ; 60(6): 188-192, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38661078

ABSTRACT

BACKGROUND: Typhoid is endemic in many low-income countries, including in Papua New Guinea. This study aimed to describe the burden and clinical features of typhoid in children in a provincial hospital, to describe environmental conditions that lead to typhoid, and to document the antibiotic sensitivity of Salmonella spp. in the Eastern Highlands Province. METHODS: A combined retrospective and prospective study of children admitted to with clinical features of typhoid to the Goroka Hospital throughout 2022. RESULTS: The study included 98 children, of which 54% were female. The median age was 8 (IQR 5-10.6) years. Over 60% of the patients were from Goroka District, the peri-urban area encompassing the town and surrounds. Ninety-four percent (92) of the patients used a pit latrine as a toilet and only 28% had access to treated water. Neuropsychiatric symptoms were common (60%), as was leukopenia (48%), thrombocytopenia (52%) and anaemia (42%). Thirty-seven patients had positive blood cultures for Salmonella typhi; all isolates were sensitive to third-generation cephalosporins, pefloxacin, ampicillin, trimethoprim and sulfamethoxazole, and only 54% sensitive to chloramphenicol. The median duration of hospitalisation was 6 days (IQR). There were no deaths. CONCLUSION: Prompt public health actions are needed to reduce the burden of typhoid infection in the Papua New Guinea. The conjugate typhoid vaccine should be considered in the highlands region, where typhoid is most endemic.


Subject(s)
Typhoid Fever , Humans , Typhoid Fever/epidemiology , Typhoid Fever/drug therapy , Typhoid Fever/diagnosis , Papua New Guinea/epidemiology , Female , Male , Child , Child, Preschool , Retrospective Studies , Prospective Studies , Salmonella typhi/isolation & purification , Salmonella typhi/drug effects , Anti-Bacterial Agents/therapeutic use
15.
Expert Opin Ther Targets ; 28(4): 323-334, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38639582

ABSTRACT

OBJECTIVES: Salmonella Typhibiofilm condition is showing as a major public health problem due to the development of antibiotic resistance and less available druggable target proteins. Therefore, we aimed to identify some more druggable targets of S. Typhibiofilm using computational drilling at the genome/proteome level so that the target shortage problem could be overcome and more antibiofilm agents could be designed in the future against the disease. METHODS: We performed protein-protein docking and interaction analysis between the homological identified target proteins of S.Typhi biofilm and a therapeutic protein L-Asparaginase. RESULTS: We have identified some druggable targets CsgD, BcsA, OmpR, CsgG, CsgE, and CsgF in S.Typhi. These targets showed high-binding affinity BcsA (-219.8 Kcal/mol) >csgF (-146.52 Kcal/mol) >ompR (-135.68 Kcal/mol) >CsgE (-134.66 Kcal/mol) >CsgG (-113.81 Kcal/mol) >CsgD(-95.39 Kcal/mol) with therapeutic enzyme L-Asparaginase through various hydrogen-bonds and salt-bridge. We found six proteins of S. Typhi biofilm from the Csg family as druggable multiple targets. CONCLUSION: This study provides insight into the idea of identification of new druggable targets and their multiple targeting with L-Asparaginase to overcome target shortage in S. Typhibiofilm-mediated infections. Results further indicated that L-Asparaginase could potentially be utilized as an antibiofilm biotherapeutic agent against S.Typhi.


Subject(s)
Anti-Bacterial Agents , Asparaginase , Biofilms , Molecular Docking Simulation , Salmonella typhi , Biofilms/drug effects , Asparaginase/pharmacology , Asparaginase/isolation & purification , Salmonella typhi/drug effects , Humans , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Drug Design , Molecular Targeted Therapy , Drug Resistance, Bacterial
16.
PLoS Negl Trop Dis ; 18(4): e0012132, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38630840

ABSTRACT

BACKGROUND: Typhoid fever is a common cause of febrile illness in low- and middle-income countries. While multidrug-resistant (MDR) Salmonella Typhi (S. Typhi) has spread globally, fluoroquinolone resistance has mainly affected Asia. METHODS: Consecutively, 1038 blood cultures were obtained from patients of all age groups with fever and/or suspicion of serious systemic infection admitted at Mnazi Mmoja Hospital, Zanzibar in 2015-2016. S. Typhi were analyzed with antimicrobial susceptibility testing and with short read (61 strains) and long read (9 strains) whole genome sequencing, including three S. Typhi strains isolated in a pilot study 2012-2013. RESULTS: Sixty-three S. Typhi isolates (98%) were MDR carrying blaTEM-1B, sul1 and sul2, dfrA7 and catA1 genes. Low-level ciprofloxacin resistance was detected in 69% (43/62), with a single gyrase mutation gyrA-D87G in 41 strains, and a single gyrA-S83F mutation in the non-MDR strain. All isolates were susceptible to ceftriaxone and azithromycin. All MDR isolates belonged to genotype 4.3.1 lineage I (4.3.1.1), with the antimicrobial resistance determinants located on a composite transposon integrated into the chromosome. Phylogenetically, the MDR subgroup with ciprofloxacin resistance clusters together with two external isolates. CONCLUSIONS: We report a high rate of MDR and low-level ciprofloxacin resistant S. Typhi circulating in Zanzibar, belonging to genotype 4.3.1.1, which is widespread in Southeast Asia and African countries and associated with low-level ciprofloxacin resistance. Few therapeutic options are available for treatment of typhoid fever in the study setting. Surveillance of the prevalence, spread and antimicrobial susceptibility of S. Typhi can guide treatment and control efforts.


Subject(s)
Anti-Bacterial Agents , Ciprofloxacin , Drug Resistance, Multiple, Bacterial , Genotype , Microbial Sensitivity Tests , Salmonella typhi , Typhoid Fever , Humans , Salmonella typhi/genetics , Salmonella typhi/drug effects , Salmonella typhi/isolation & purification , Salmonella typhi/classification , Ciprofloxacin/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Anti-Bacterial Agents/pharmacology , Typhoid Fever/microbiology , Typhoid Fever/epidemiology , Tanzania/epidemiology , Adolescent , Male , Child , Adult , Young Adult , Female , Child, Preschool , Whole Genome Sequencing , Middle Aged , Infant , Aged
17.
Infect Disord Drug Targets ; 24(6): e230124225976, 2024.
Article in English | MEDLINE | ID: mdl-38265374

ABSTRACT

BACKGROUND: Typhoid fever poses a significant health challenge in low- and middleincome countries (LMiCs), impacting millions of individuals across various age groups. Its prevalence is particularly pronounced in South Asia. Factors contributing to its transmission in South Asia include rapid unplanned urbanization, urban-rural disparities, provision of poor water and sanitation facilities, and open defecation. The mortality rate of typhoid fever is up to 1%, and those who survive have a protracted period of poor health and carry an enormous financial burden. The treatment is further complicated by the emerging antibiotic resistance leaving few treatment options in hands. This issue has become more urgent due to the further emergence of extended drug-resistant (XDR) and multidrug-resistant (MDR) typhoid strains, as well as their subsequent global spread. Fluoroquinolone-resistant Salmonella spp. is currently classified by the World Health Organization (WHO) as a high (Priority 2) pathogen. As a result, establishing minimum inhibitory concentrations (MIC) according to the latest guidelines may prove effective in treating typhoid fever and minimizing the rising threat of drug resistance.


Subject(s)
Anti-Bacterial Agents , Developing Countries , Drug Resistance, Multiple, Bacterial , Microbial Sensitivity Tests , Salmonella typhi , Typhoid Fever , Humans , Typhoid Fever/drug therapy , Typhoid Fever/microbiology , Typhoid Fever/epidemiology , Salmonella typhi/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Fluoroquinolones/pharmacology , Fluoroquinolones/therapeutic use
18.
Ir J Med Sci ; 193(3): 1377-1384, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38158479

ABSTRACT

BACKGROUND: Typhoid fever is a fatal disease in humans that is caused by Salmonella typhi. S. typhi infections need immediate antibiotic therapy, and their extensive use has led to multidrug-resistant (MDR) pathogens. The use of bacteriophages is becoming a new way to treat these resistant bacteria. This research was directed to bacteriophage isolation against S. typhi and to determine phage-antibiotic synergism. AIMS: To isolate bacteriophages targeting S. typhi, the causative agent of typhoid fever, and investigate their potential synergistic effects when combined with antibiotics. STUDY DESIGN: A cross-sectional study. METHODS: The Widal test was positive; twenty diarrheal stool samples were taken, and for confirmation of S. typhi, different biochemical tests were performed. The disc-diffusion technique was used to determine antimicrobial resistance, and the double agar overlay method was used for bacteriophage isolation from sewage water against S. typhi. To test antibiotic-phage synergism, the S. typhi bacteria was treated by phages together with varying antibiotic concentrations. RESULTS: Eleven samples were positive for S. typhi with black colonies on SS-agar. These were catalase and MR positive with alkali butt on TSI. Clear plaques were observed after the agar overlay. Isolated phages were stable at various pH and temperature levels. Synergism was observed on agar plate. The zone was enlarged when phages were combined with bacterial lawn culture and ciprofloxacin disk. Bacterial growth inhibition had a significant p-value of 0.03 in titration plates, with the phage-ciprofloxacin combination being more effective than the phage and antibiotic alone. CONCLUSION: The study highlights the synergistic effects of isolated bacteriophages with antibiotics, which are not only effective against S. typhi infection but also decrease antibiotic resistance.


Subject(s)
Anti-Bacterial Agents , Feces , Salmonella typhi , Typhoid Fever , Salmonella typhi/drug effects , Salmonella typhi/isolation & purification , Humans , Typhoid Fever/microbiology , Typhoid Fever/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cross-Sectional Studies , Feces/microbiology , Feces/virology , Bacteriophages/isolation & purification , Microbial Sensitivity Tests , Phage Therapy/methods
19.
BMC Microbiol ; 23(1): 25, 2023 01 21.
Article in English | MEDLINE | ID: mdl-36681806

ABSTRACT

Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor hygienic environments. To find novel therapeutic targets and inhibitors, We employed a subtractive genomics strategy towards Salmonella Typhi and the complete genomes of eight strains were primarily subjected to the EDGAR tool to predict the core genome (n = 3207). Human non-homology (n = 2450) was followed by essential genes identification (n = 37). The STRING database predicted maximum protein-protein interactions, followed by cellular localization. The virulent/immunogenic ability of predicted genes were checked to differentiate drug and vaccine targets. Furthermore, the 3D models of the identified putative proteins encoded by the respective genes were constructed and subjected to druggability analyses where only "highly druggable" proteins were selected for molecular docking and simulation analyses. The putative targets ATP-dependent CLP protease proteolytic subunit, Imidazole glycerol phosphate synthase hisH, 7,8-dihydropteroate synthase folP and 2,3-bisphosphoglycerate-independent phosphoglycerate mutase gpmI were screened against a drug-like library (n = 12,000) and top hits were selected based on H-bonds, RMSD and energy scores. Finally, the ADMET properties for novel inhibitors ZINC19340748, ZINC09319798, ZINC00494142, ZINC32918650 were optimized followed by binding free energy (MM/PBSA) calculation for ligand-receptor complexes. The findings of this work are expected to aid in expediting the identification of novel protein targets and inhibitors in combating typhoid Salmonellosis, in addition to the already existing therapies.


Subject(s)
Anti-Bacterial Agents , Salmonella typhi , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Endopeptidase Clp , Genomics , Molecular Docking Simulation , Salmonella typhi/drug effects , Salmonella typhi/genetics , Typhoid Fever
20.
Afr Health Sci ; 23(4): 177-182, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38974275

ABSTRACT

Background: The emanation of multi-drugs resistant microorganisms and the challenges faced in combating multi-drug resistant infections is a public health issue and this has increased the search for effective antibiotics from natural sources. Objectives: This work aims to determine the susceptibility of some pathogenic bacterial species to snail slime. Methods: The antibacterial activity of aqueous and ethanolic snail slime extracts were investigated against Staphylococcus aureus, Salmonella typhi, Bacillus subtilis and Escherichia coli using the agar well diffusion method. Results: The results showed that all the organisms were sensitive to both extracts but were more susceptible to aqueous extracts; the highest zone of inhibition for aqueous extracts was 27.33mm ± 2.51mm for Staphylococcus aureus at concentration of 1000µl/ml, while the lowest was 11.33mm ± 1.53mm against Escherichia coli. The highest zone of inhibition for ethanolic fraction was 15.67 ± 1.15mm for Salmonella typhi. The lowest inhibition was 9.33mm ± 0.58mm for Escherichia coli. The MIC was 3.125% for Staphylococcus aureus, Bacillus subtilis and Escherichia coli and 6.25% for S. typhi. The extracts were not cidal at the concentrations used. Statistical analysis revealed that the treatments between the aqueous and ethanolic extracts against Staphylococcus aureus, Escherichia coli and Salmonella typhi were significant (p ≤ 0.05). The treatment against B. subtilis showed no significant difference between the two extracts (p > 0.05). Conclusion: This study has revealed that snail slime possesses antibacterial properties which can be used as anti-microbial agents against infectious diseases.


Subject(s)
Anti-Bacterial Agents , Bacillus subtilis , Escherichia coli , Microbial Sensitivity Tests , Salmonella typhi , Snails , Staphylococcus aureus , Escherichia coli/drug effects , Salmonella typhi/drug effects , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Animals , Snails/microbiology , Humans
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