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PloS One 2024Typhoid fever, caused by Salmonella enterica serovar typhi, presents a substantial global health threat, particularly in regions with limited healthcare infrastructure....
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.
Topics: Salmonella typhi; Drug Resistance, Multiple, Bacterial; Lignans; Anti-Bacterial Agents; Bacterial Proteins; Humans; Microbial Sensitivity Tests; Computational Biology
PubMed: 38917154
DOI: 10.1371/journal.pone.0303285 -
Microbiology Spectrum Jun 2024The aim of the present study was first to isolate from gastric biopsy specimens and to test their antibiotic susceptibility. Second, it was to evaluate the efficacy of...
The aim of the present study was first to isolate from gastric biopsy specimens and to test their antibiotic susceptibility. Second, it was to evaluate the efficacy of the standard triple therapy from patients of the west central region of Colombia. positive patients received standard triple therapy with proton pump inhibitor (PPI) (40 mg b.i.d.), clarithromycin (500 mg b.i.d.), and amoxicillin (1 g b.i.d.) for 14 days. Thereafter, antibiotic susceptibility of the isolates was assessed by E-Test. From 94 patients enrolled, 67 were positive for by histology or culture. Overall resistance to metronidazole, levofloxacin, rifampicin, clarithromycin, and amoxicillin was 81%, 26.2%, 23.9%, 19%, and 9.5%, respectively. No resistance was found for tetracycline. A total of 54 patients received standard triple therapy, 48 attended follow-ups testing, and of them, 30 had resistance test reports. Overall eradication rate was 81.2%. Second-line treatment was given to eight patients, four of whom were followed up with a 13C urea breath test (UBT) and remained positive for . Eradication was significantly higher in patients with clarithromycin susceptible than in resistant strains (95.6% vs 42.8% = 0.001). The updated percentages of resistance to clarithromycin in this geographical area had increased, so this value must be considered when choosing the treatment regimen.IMPORTANCEAntibiotic resistance in has increased worldwide, as has resistance to multiple antimicrobials (MDRs), which seriously hampers the successful eradication of the infection. The ideal success rate in eradicating infection (≥90%) was not achieved in this study (81.2%). This is the first time that MDR is reported (14.3%) in the region; the resistance to clarithromycin increased over time (3.8%-19%), and levofloxacin (26.2%) and rifampicin (23%) resistant isolates were detected for the first time. With these results, strain susceptibility testing is increasingly important, and the selection of treatment regimen should be based on local antibiotic resistance patterns.
PubMed: 38916348
DOI: 10.1128/spectrum.00401-24 -
Frontiers in Cellular and Infection... 2024The naturally occurring dipeptide Tryptophylglycine (WG) is enhanced in human immunodeficiency virus (HIV-1) infected Elite Controllers (EC). We have shown that this...
INTRODUCTION
The naturally occurring dipeptide Tryptophylglycine (WG) is enhanced in human immunodeficiency virus (HIV-1) infected Elite Controllers (EC). We have shown that this dipeptide has an anti-HIV-1 effect and evaluated now its synergistic antiretroviral activity, in combination with current antiretrovirals against multi-drug resistant HIV-1 isolates.
METHODS
Drug selectivity assay with WG-am and ARVs agains HIV-1 resistant isolates were carried out. Subsequently, two methods, Chou-Talalay's Combination Index (CI) and ZIP synergy score (SS), were used to quantify the synergism.
RESULTS
WG-am had a moderate/strong synergism with the four tested antiretrovirals: raltegravir, tenofovir, efavirenz, darunavir. WG-am:TDF had strong synergism at ED50, ED75, ED90 (CI: <0.2) in isolates resistant to protease inhibitors or integrase strand inhibitors (INSTI), and a slightly less synergism in isolates resistant to non-nucleoside or nucleotide reverse transcriptase inhibitors. WG-am combined with each of the four drugs inhibited all drug-resistant isolates with over 95% reduction at maximum concentration tested. The highest selectivity indexes (CC50/ED50) were in INSTI-resistant isolates.
CONCLUSION
Our data suggest that WG, identified as occurring and enhanced in Elite Controllers has a potential to become a future treatment option in patients with HIV-1 strains resistant to any of the four major categories of anti-HIV-1 compounds.
Topics: HIV-1; Drug Synergism; Humans; Dipeptides; HIV Infections; Anti-HIV Agents; Microbial Sensitivity Tests; Drug Resistance, Viral
PubMed: 38915925
DOI: 10.3389/fcimb.2024.1334126 -
BioRxiv : the Preprint Server For... Jun 2024HflX is known to rescue stalled ribosomes and is implicated in antibiotic resistance in several bacteria. Here we present several high-resolution cryo-EM structures of...
HflX is known to rescue stalled ribosomes and is implicated in antibiotic resistance in several bacteria. Here we present several high-resolution cryo-EM structures of mycobacterial HflX in complex with the ribosome and its 50S subunit, with and without antibiotics. These structures reveal a distinct mechanism for HflX- mediated ribosome splitting and antibiotic resistance in mycobacteria. In addition to dissociating ribosome into two subunits, mycobacterial HflX mediates persistent disordering of multiple 23S rRNA helices to generate an inactive pool of 50S subunits. Mycobacterial HflX also acts as an anti-association factor by binding to pre-dissociated 50S subunits. A mycobacteria-specific insertion in HflX reaches further into the peptidyl transferase center. The position of this insertion overlaps with ribosome-bound macrolides or lincosamide class of antibiotics. The extended conformation of insertion seen in the absence of these antibiotics retracts and adjusts around the bound antibiotics instead of physically displacing them. It therefore likely imparts antibiotic resistance by sequestration of the antibiotic- bound inactive 50S subunits.
PubMed: 38915643
DOI: 10.1101/2024.06.13.598844 -
RSC Advances Jun 2024Multidrug-resistant bacteria resulting from the abuse and overuse of antibiotics have become a huge crisis in global public health security. Therefore, it is urgently...
Multidrug-resistant bacteria resulting from the abuse and overuse of antibiotics have become a huge crisis in global public health security. Therefore, it is urgently needed to develop new antibacterial drugs with unique mechanisms of action. As a versatile moiety, morpholine has been widely employed to enhance the potency of numerous bioactive molecules. In this study, a series of ruthenium-based antibacterial agents modified with the morpholine moiety were designed and characterized, aiming to obtain a promising metalloantibiotic with a multitarget mechanism. Antibacterial activity screening demonstrated that the most active complex Ru(ii)-3 exhibited the strongest potency against () with an MIC value of only 0.78 μg mL, which is better than most clinically used antibiotics. Notably, Ru(ii)-3 not only possessed excellent bactericidal efficacy, but could also overcome bacterial resistance. Importantly, Ru(ii)-3 very efficiently removed biofilms produced by bacteria, inhibited the secretion of bacterial exotoxins, and enhanced the activity of many existing antibiotics. The results of mechanism studies confirmed that Ru(ii)-3 could destroy the bacterial membrane and induce ROS production in bacteria. Furthermore, animal infection models confirmed that Ru(ii)-3 showed significant anti-infective activity . Overall, this work demonstrated that a morpholine-modified ruthenium-based agent is a promising antibiotic candidate in tackling the crisis of drug-resistant bacteria.
PubMed: 38915333
DOI: 10.1039/d4ra02667e -
BMC Infectious Diseases Jun 2024Virological failure, drug resistance, toxicities, and other issues make it difficult for ART to maintain long-term sustainability. These issues would force a...
BACKGROUND
Virological failure, drug resistance, toxicities, and other issues make it difficult for ART to maintain long-term sustainability. These issues would force a modification in the patient's treatment plan. The aim of this research was to determine whether first-line antiretroviral therapy is durable and to identify the factors that lead to patients on HAART changing their first highly active antiretroviral therapy regimen.
METHODS
A retrospective cohort study was conducted from October, 2019-March, 2020 across all regional states including Addis Ababa and Dire Dawa administrative cities. The target population is from all health facilities that have been providing ART service for at least the past 6 months as of October 2019. Multi-stage clustered sampling method was used to select study facilities and participants. Simple random selected ART medical records of patients ever enrolled in ART treatment services. We adopted a multi-state survival modelling (msm) approach assuming each treatment regimen as state. We estimate the transition probability of patients to move from one regimen to another for time to treatment change/switch. We estimated the transition probability, prediction probabilities and length of stay and factor associated with treatment modification of patients to move from one regimen to another.
RESULTS
Any of the six therapy combinations (14.4%) altered their treatment at least once during the follow-up period for a variety of reasons. Of the patients, 4,834 (13.26%) changed their treatments just once, while 371 (1.1%) changed it more than once. For 38.6% of the time, a treatment change was undertaken due to toxicity, another infection or comorbidity, or another factor, followed by New drugs were then made accessible and other factors 18.3% of the time, a drug was out of supply; 2.6% of those instances involved pregnancy; and 43.1% involved something else. Highly active anti-retroviral therapy (HAART) combinations TDF + 3TC + NVP, d4T + 3TC + NVP, and TDF + 3TC + EFV were high to treatment alterations in all reasons of treatment modifications, with 29.74%, 26.52%, and 19.52% treatment changes, respectively. Early treatment modification or regime change is one of the treatment combinations that include the d4T medication that creates major concern. The likelihood of staying and moving at the the start of s = 0 and 30-month transitions increased, but the likelihood of staying were declined. For this cohort dataset, the presence of opportunistic disease, low body weight, baseline CD4 count, and baseline TB positive were risk factors for therapy adjustment.
CONCLUSION
Given that the current study took into account a national dataset, it provides a solid basis for ART drug status and management. The patient had a higher likelihood of adjusting their treatment at some point during the follow-up period due to drug toxicity, comorbidity, drug not being available, and other factors, according to the prediction probability once more. Baseline TB positivity, low CD4 count, opportunistic disease, and low body weight were risk factors for therapy adjustment in this cohort dataset.
Topics: Humans; Ethiopia; Retrospective Studies; Female; Male; Adult; HIV Infections; Antiretroviral Therapy, Highly Active; Anti-HIV Agents; Markov Chains; Time-to-Treatment; Middle Aged; Young Adult; Acquired Immunodeficiency Syndrome; Adolescent
PubMed: 38914968
DOI: 10.1186/s12879-024-09469-9 -
Scientific Reports Jun 2024Stenotrophomonas maltophilia is a nonfermenting gram-negative bacterium associated with multiple nosocomial outbreaks. Antibiotic resistance increases healthcare costs,...
Stenotrophomonas maltophilia is a nonfermenting gram-negative bacterium associated with multiple nosocomial outbreaks. Antibiotic resistance increases healthcare costs, disease severity, and mortality. Multidrug-resistant infections (such as S. maltophilia infection) are difficult to treat with conventional antimicrobials. This study aimed to investigate the isolation rates, and resistance trends of S. maltophilia infections over the past 19 years, and provide future projections until 2030. In total, 4466 patients with S. maltophilia infection were identified. The adult and main surgical intensive care unit (ICU) had the highest numbers of patients (32.2%), followed by the cardiology department (29.8%), and the paediatric ICU (10%). The prevalence of S. maltophilia isolation increased from 7% [95% confidence interval (CI) 6.3-7.7%] in 2004-2007 to 15% [95% CI 10.7-19.9%] in 2020-2022. Most S. maltophilia isolates were resistant to ceftazidime (72.5%), levofloxacin (56%), and trimethoprim-sulfamethoxazole (14.05%), according to our study. A consistent and significant difference was found between S. maltophilia-positive ICU patients and non-ICU patients (P = 0.0017) during the three-year pandemic of COVID-19 (2019-2021). The prevalence of S. maltophilia isolates is expected to reach 15.08% [95% CI 12.58-17.59%] by 2030. Swift global action is needed to address this growing issue; healthcare authorities must set priorities and monitor infection escalations and treatment shortages.
Topics: Stenotrophomonas maltophilia; Humans; Gram-Negative Bacterial Infections; Retrospective Studies; Prevalence; Anti-Bacterial Agents; Male; Female; Adult; Microbial Sensitivity Tests; Middle Aged; Drug Resistance, Multiple, Bacterial; Intensive Care Units; COVID-19; Child; Drug Resistance, Bacterial; Aged; Cross Infection
PubMed: 38914597
DOI: 10.1038/s41598-024-65509-z -
PloS One 2024The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the...
The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the properties of neural precursor cells during their maturation and migration process. An increasing number of neurotransmitters and biomolecules have been identified as molecular signals that trigger and guide this process. In this sense, taurine, a sulfur-containing, non-essential amino acid widely expressed in the mammal brain, modulates the neuronal differentiation process. In this study, we describe the effect of taurine acting via the ionotropic GABAA receptor and the metabotropic GABAB receptor on the neuronal differentiation and electrophysiological properties of precursor cells derived from the subventricular zone of the mouse brain. Taurine stimulates the number of neurites and favors the dendritic complexity of the neural precursor cells, accompanied by changes in the somatic input resistance and the strength of inward and outward membranal currents. At the pharmacological level, the blockade of GABAA receptors inhibits these effects, whereas the stimulation of GABAB receptors has no positive effects on the taurine-mediated differentiation process. Strikingly, the blockade of the GABAB receptor with CGP533737 stimulates neurite outgrowth, dendritic complexity, and membranal current kinetics of neural precursor cells. The effects of taurine on the differentiation process involve Ca2+ mobilization and the activation of intracellular signaling cascades since chelation of intracellular calcium with BAPTA-AM, and inhibition of the CaMKII, ERK1/2, and Src kinase inhibits the neurite outgrowth of neural precursor cells of the subventricular zone.
Topics: Animals; Neural Stem Cells; Receptors, GABA-B; Mice; Cell Differentiation; Receptors, GABA-A; Lateral Ventricles; Taurine; Neurogenesis; Calcium
PubMed: 38913632
DOI: 10.1371/journal.pone.0305853 -
MBio Jun 2024Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been...
Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the () and increased copies of (). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) allele and a single copy of , while KH004 has a chloroquine-resistant (Dd2-like) allele with an additional G367C substitution and multiple copies of . We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at and . We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC. We find that inheritance of the KH004 allele is required for reduced PPQ sensitivity, whereas copy number variation in further decreases susceptibility but does not confer resistance in the absence of additional mutations in . A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions , , and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter.IMPORTANCEResistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 was inherited among the progeny clones, allowing us to directly test the role of the copy number on resistance-related phenotypes in the context of a unique allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.
PubMed: 38912775
DOI: 10.1128/mbio.00805-24 -
Frontiers in Cellular and Infection... 2024Widespread opportunistic pathogens pose a serious threat to global health, particularly in susceptible hospital populations. The escalating crisis of antibiotic...
INTRODUCTION
Widespread opportunistic pathogens pose a serious threat to global health, particularly in susceptible hospital populations. The escalating crisis of antibiotic resistance highlights the urgent need for novel antibacterial agents and alternative treatment approaches. Traditional Chinese Medicine (TCM) and its compounds have deep roots in the treatment of infectious diseases. It has a variety of active ingredients and multi-target properties, opening up new avenues for the discovery and development of antimicrobial drugs.
METHODS
This study focuses on assessing the efficacy of the Shensheng-Piwen changed medicinal powder (SPC) extracts against opportunistic pathogen infections by broth microdilution and agar disc diffusion methods. Additionally, biofilm inhibition and eradication assays were performed to evaluate the antibiofilm effects of SPC extracts.
RESULTS
Metabolite profiles were analyzed by LC-MS. Furthermore, the potential synergistic effect between SPC and Metal-Organic Framework (MOF) was investigated by bacterial growth curve analysis. The results indicated that the SPC extracts exhibited antibacterial activity against , with a minimum inhibitory concentration (MIC) of 7.8 mg/mL (crude drug concentration). Notably, at 1/2 MIC, the SPC extracts significantly inhibited biofilm formation, with over 80% inhibition, which was critical in tackling chronic and hospital-acquired infections. Metabolomic analysis of revealed that SPC extracts induced a notable reduction in the levels of various metabolites, including L-proline, L-asparagine. This suggested that the SPC extracts could interfere with the metabolism of . Meanwhile, the growth curve experiment proved that SPC extracts and MOFs had a synergistic antibacterial effect.
DISCUSSION
In conclusion, the present study highlights the potential of SPC extracts as a novel antibacterial agent against infections, with promising biofilm inhibition properties. The observed synergistic effect between SPC extracts and MOFs further supports the exploration of this combination as an alternative treatment approach.
Topics: Anti-Bacterial Agents; Biofilms; Microbial Sensitivity Tests; Metal-Organic Frameworks; Drugs, Chinese Herbal; Staphylococcus aureus; Drug Synergism; Powders; Humans; Chromatography, Liquid
PubMed: 38912207
DOI: 10.3389/fcimb.2024.1376312