Computational Mutagenesis and Inhibition of Staphylococcus aureus AgrA LytTR Domain Using Phenazine Scaffolds: Insight From a Biophysical Study.

Biofilm formation by Staphylococcus aureus is a major challenge in clinical settings due to its role in persistent infections. The AgrA protein, a key regulator in biofilm development, is a promising target for therapeutic intervention. This study investigates the antibiofilm potential of halogenated phenazine compounds by targeting AgrA and explores their molecular interactions to provide insights for drug development. We employed molecular docking, molecular dynamics simulations, and computational mutagenesis to evaluate the binding of halogenated phenazine compounds (C1 to C7, HP, and HP-14) to AgrA. Binding free energy analysis was performed to assess the affinity of these compounds for the AgrA-DNA complex. Additionally, the impact of these compounds on AgrA's structural conformation and salt bridge interactions was examined. The binding-free energy analysis revealed that all compounds enhance binding affinity compared to the Apo form of AgrA, which has a ΔGbind of -80.75 kcal/mol. The strongest binding affinities were observed with compounds C7 (-113.84 kcal/mol), HP-14 (-115.23 kcal/mol), and HP (-112.28 kcal/mol), highlighting their effectiveness. Molecular dynamics simulations demonstrated that these compounds bind at the hydrophobic cleft of AgrA, disrupting essential salt bridge interactions between His174-Glu163 and His174-Glu226. This disruption led to structural conformational changes and reduced DNA binding affinity, aligning with experimental findings on biofilm inhibition. The halogenated phenazine compounds effectively inhibit biofilm formation by targeting AgrA, disrupting its DNA-binding function. The study supports the potential of these compounds as antibiofilm agents and provides a foundation for rational drug design targeting the AgrA-DNA interaction. Future research should focus on further optimizing these lead compounds and exploring additional active sites on AgrA to develop novel treatments for biofilm-associated infections.

Eosinophil: An innate immune cell with anti-filarial vaccine and biomarker potential.

Background: Filarial infections continue to pose a great challenge in endemic countries. One of the central goals in the fight against human filarial infections is the development of strategies that will lead to the inhibition of microfilariae (mf) transmission. Keeping mf under a certain threshold within endemic populations will stop transmission and eliminate the infection. Method: A narrative review was carried out to identify the possibilities and limitations of exploring the use of eosinophil responses as an anti-filarial vaccine, and biomarker for the detection of filarial infections. An extensive literature search was performed in online scientific databases including PubMed Central, PubMed, BioMed Central, with the use of predefined search terms. Results: A better understanding of the parasite-host interactions will lead to the development of improved and better treatment or vaccine strategies that could eliminate filariasis as soon as possible. Highlighted in this review is the explorative use of eosinophil-producing CLC/Galectin-10 as a potential biomarker for filarial infections. Also discussed are some genes, and pathways involved in eosinophil recruitments that could be explored for anti-filarial vaccine development. Conclusion: In this short communication, we discuss how eosinophil-regulated genes, pathways, and networks could be critical in providing more information on how reliably a front-line immune player could be exploited for anti-filarial vaccine development and early infection biomarker.

Use of medicinal plants as a remedy against lymphatic filariasis: Current status and future prospect.

Despite the successes achieved so far with the Global Programme to Eliminate Lymphatic Filariasis, there is still an appreciable number of lymphatic filarial patients who need alternative treatment and morbidity management strategies. The unresponsiveness of some cohorts to the drugs used in the mass drug administration program is currently raising a lot of questions and this needs urgent attention. Natural medicinal plants have a long-standing history of being effective against most disease conditions. Countries such as India have been able to integrate their natural plant remedies into the treatment of lymphatic filarial conditions, and the results are overwhelmingly positive. Components of Azadirachta indica A. Juss, Parkia biglobosa, Adansonia digitata, and Ocimum spp have been shown to have anti-inflammatory, anticancerous, and antimicrobial activities in animal models. Therefore, this review calls for attention toward the use of natural plant components as an alternate treatment against lymphatic filariasis to help reduce the World Health Organization's burden of providing drugs for people in need of treatment every year.

Knowledge and perceptions of lymphatic filariasis patients in selected hotspot endemic communities in southern Ghana.

Lymphatic filariasis (LF) is a mosquito-borne neglected tropical disease that is one of the leading global causes of permanent disability. To date, LF interventions have been largely biomedical, focusing on drug treatments to disrupt parasite transmission and manage disease morbidity. Although important, these Mass Drug Administration (MDA) programs neglect the significance of socio-economic burden to the health of LF patients, which are compounded by social stigmatization, discrimination and associated depressive illnesses. The MDA program also typically fails to engage with local community beliefs and perceptions of LF, which may differ markedly from biomedical explanations and may have fueled non-compliance to treatments which is one of the major challenges of the Mass Drug Administration program. LF is not only a biomedical issue but also a social issue and LF interventions need to understand people's world views and the contexts through which they interpret bodily maladies. Hence, an effective LF intervention must bring together both the biomedical and the social components. The goal of this exploratory study was to assist in refining a large qualitative study (currently underway) that seeks to integrate culturally appropriate LF interventions into current LF control programs in Ghana. In this paper, we discuss the findings of a pre-intervention, exploratory study aimed at gaining a baseline grasp of a local culturally informed understanding of lymphatic filariasis and the knowledge gaps looking at three endemic Ghanaian communities in the Ahanta West District. A structured questionnaire was employed to assess the wellbeing, social inclusion, and cultural understanding of LF with a geographic focus within LF-endemic areas in Ghana. Interestingly, 45.8% of the 72 participants reported to have received information about LF from health care providers and the MDA program but only 5 out of the 72 (6.9%) respondents believed that LF was transmitted by mosquitos. This baseline study revealed several alternative interpretations and misconceptions about the disease, as well as the social and economic impacts, and importantly, the need to integrate qualitative research to develop culturally appropriate interventions and increase engagement with existing control programs.

Antibiotic resistance and mecA characterization of Staphylococcus hominis from filarial lymphedema patients in the Ahanta West District, Ghana: A cross-sectional study.

Background and Aim: Filarial infections affect over 150 million people in the tropics. One of the major forms of filarial pathologies is lymphedema; a condition where the immune response is significantly altered, resulting in changes in the normal flora. Staphylococcus hominis, a human skin commensal, can also be pathogenic in immunocompromised individuals. Therefore, there is the possibility that S. hominis could assume a different behavior in filarial lymphedema patients. To this end, we investigated the levels of antibiotic resistance and extent of mecA gene carriage in S. hominis among individuals presenting with filarial lymphedema in rural Ghana. Method: We recruited 160 individuals with stages I-VII lymphedema, in a cross-sectional study in the Ahanta West District of the Western Region of Ghana. Swabs from lymphedematous limb ulcers, pus, and cutaneous surfaces were cultured using standard culture-based techniques. The culture isolates were subjected to Matrix-Assisted Laser Desorption/Ionization Time of Flight (MALDI-TOF) mass spectrometry for bacterial identification. Antimicrobial susceptibility testing (AST) was performed using the Kirby-Bauer method. mecA genes were targeted by polymerase chain reaction for strains that were cefoxitin resistant. Results: In all, 112 S. hominis were isolated. The AST results showed resistance to chloramphenicol (87.5%), tetracycline (83.3%), penicillin (79.2%), and trimethoprim/sulphamethoxazole (45.8%). Of the 112 strains of S. hominis, 51 (45.5%) were resistant to cefoxitin, and 37 (72.5%) of the cefoxitin-resistant S. hominis haboured the mecA gene. Conclusion: This study indicates a heightened level of methicillin-resistant S. hominis isolated among filarial lymphedema patients. As a result, opportunistic infections of S. hominis among the already burdened filarial lymphedema patients in rural Ghana may have reduced treatment success with antibiotics.