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Disulfiram Attenuates Acinetobacter baumannii-Induced Hyperinflammation by Regulating Inflammatory Pathways: Insights from RNA Sequencing
Authors: Divyasree Vulli
Abstract
The emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) poses a major obstacle in treating sepsis, highlighting the urgent need for new therapeutic approaches. Recent studies have reported that disulfiram (DSF) exhibits antibacterial activity and potentiates meropenem activity against resistant A. baumannii (A. baumannii) isolates. The mechanisms by which DSF modulates inflammation during A. baumannii infection remain unclear, although DSF possesses anti-inflammatory properties by regulating the pyroptosis pathway. The present study aimed to investigate the potential effect of DSF in modulating inflammatory responses during CRAB infection. We observed DSF treatment in A. baumannii-infected cells resulted in inhibiting NF-κB activity and NLRP3 inflammasome formation, which decreases expression and secretion of IL-1β, IL-6, and TNF-α in human THP-1 cell-derived macrophages. Further, RNA sequencing was performed to determine how DSF suppresses the CRAB-associated inflammation. The transcriptomic data analysis revealed downregulation of genes involved in inflammatory pathways, including the NF-κB signaling pathway, toll-like receptor signaling pathway, and cytokine–cytokine receptor interaction pathway, in DSF-treated cells, which indicates its anti-inflammatory effects in suppressing A. baumannii-induced inflammation. Collectively, our findings demonstrate that DSF is a promising candidate for modulating inflammatory responses during CRAB infection; however, further validation through in vivo and clinical studies is necessary.
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Antibiotic Repurposing: Conjugation of the Gram-Positive Only Peptide Antibiotic Bacitracin to a Bis-Catechol Siderophore Mimetic Imparts Potent Activity against Multi-Drug Resistant Acinetobacter baumannii
Authors: Rui Liu
Abstract
The ongoing emergence of multidrug resistant (MDR) bacteria is a grave concern and is exacerbated by the lack of innovative antibiotics under development. One approach to enhancing antibacterial efficacy is to determine whether derivatives of antibiotics that are normally used to treat infections caused by Gram-positive bacteria might be made effective against Gram-negative bacteria by circumventing permeability barriers and antibiotic deactivation processes. Sideromycins (siderophore-antibiotic conjugates) are recognized by outer membrane protein receptors to initiate the acquisition of essential iron and are actively assimilated by Gram-negative bacteria. Azotochelin is a natural bis-catechol siderophore that is utilized by a broad spectrum of Gram-negative bacteria to sequester iron. Herein we report syntheses of a conjugate of bacitracin with a bis-catechol mimetic of azotochelin. Antibacterial activity assays revealed that coupling of bacitracin, which is only known to be active against Gram-positive bacteria, to the siderophore induced selective potent activity against MDR strains of Gram-negative Acinetobacter baumannii.
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Non-adherence and its predictors among pediatric household contacts on tuberculosis preventive therapy in the 3HP era: A multicenter observational study
Authors: Woretaw Sisay Zewdu
Abstract
Background: Despite prophylactic pharmacotherapy being ranked as the best intervention yet, poor treatment adherence tempers tuberculosis preventive therapy (TPT) efficacy.
Objectives: This study aimed to investigate TPT non-adherence among household contacts and its determinants following the rollout of the 3HP regimen in northwest Ethiopia.
Design: A facility-based multicenter retrospective study was conducted in selected hospitals of northwest Ethiopia from October 17 to February 21, 2024.
Methods: Target populations were TPT-eligible household contacts (⩽15 years old) based on the national tuberculosis treatment guideline. Univariate and multivariate binary logistic regression model was fitted to identify potential predictors. p-Value < 0.05 was employed to adjudicate the significance level.
Results: Among 494 household contacts (HHCs) enrolled in this study, 27.94% were non-adherent. Age (5–10 years: adjusted odds ratio (AOR) (95% CI): 1.92 (1.05–3.19); 10–15 years: AOR (95% CI): 2.04 (1.01–4.12)), parental status (AOR (95% CI): 1.87 (1.02–5.24)), comorbidity (AOR (95% CI): 2.92 (1.08–5.69)), poor nutritional status (AOR (95% CI): 1.30 (1.06–2.43)), adverse drug reactions (AOR (95% CI): 4.01 (1.03–8.20)), adherence support (AOR (95% CI): 1.56 (1.08–6.69)) and TPT regimen type (AOR (95% CI): 4.23 (1.85–6.53)) predicts non-adherence.
Conclusion: Altogether, this study revealed a high level of non-adherence among HHCs in northwest Ethiopia, falling short of the national 2025/26 TPT targets. TPT should be accompanied by firm counseling and routine supervision to improve adherence.”
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Harm reduction in practice: baseline cohort description and early engagement trends in an incentive-based program for PWUD
Authors: Nadia Mattanah
Abstract
Background: Contingency management (CM) has been used to reinforce abstinence in the treatment of substance use disorders (SUD). Novel applications of CM in people who use drugs (PWUD) have been used to facilitate other desirable behaviors.
Objective: Describe and assess preliminary outcomes of a program intended to reduce risk for HIV and related infections in a population of PWUD through increased healthcare engagement.
Design: Patients receiving care for SUD at a collocated clinic receive shaping CM-based incentives for risk assessment, testing, and clinic attendance.
Methods: Baseline cohort characteristics are assessed, and engagement in clinical care during the early period of the program is described.
Results: Participants are majority African American, female, and meet criteria for experiencing financial resource strain. During the first year of the program, no significant changes in clinic appointment attendance were observed.
Conclusion: Patient-centered CM-based incentivization implemented in a low-barrier, harm-reduction setting may facilitate incremental health behavior changes to reduce infection-related comorbid risk. There is a need to expand approaches to those with high risk and barriers.”