The broad-spectrum antimicrobial potential of [Mn(CO)4(S2CNMe(CH2CO2H))], a water-soluble CO-releasing molecule (CORM-401): intracellular accumulation, transcriptomic and statistical analyses, and membrane Polarization

Aims: Carbon monoxide (CO)-releasing molecules (CORMs) are candidates for animal and antimicrobial therapeutics. We aimed to probe the antimicrobial potential of a novel manganese CORM. Results: [Mn(CO)4S2CNMe(CH2CO2H)], CORM-401, inhibits growth of Escherichia coli and several antibiotic-resistant clinical pathogens. CORM-401 releases CO that binds oxidases in vivo, but is an ineffective respiratory inhibitor. Extensive CORM accumulation (assayed as intracellular manganese) accompanies antimicrobial activity. CORM-401 stimulates respiration, polarizes the cytoplasmic membrane in an uncoupler-like manner, and elicits loss of intracellular potassium and zinc. Transcriptomics and mathematical modeling of transcription factor activities reveal a multifaceted response characterized by elevated expression of genes encoding potassium uptake, efflux pumps, and envelope stress responses. Regulators implicated in stress responses (CpxR), respiration (Arc, Fnr), methionine biosynthesis (MetJ), and iron homeostasis (Fur) are significantly disturbed. Although CORM-401 reduces bacterial growth in combination with cefotaxime and trimethoprim, fractional inhibition studies reveal no interaction. Innovation: We present the most detailed microbiological analysis yet of a CORM that is not a ruthenium carbonyl. We demonstrate CO-independent striking effects on the bacterial membrane and global transcriptomic responses. Conclusions: CORM-401, contrary to our expectations of a CO delivery vehicle, does not inhibit respiration. It accumulates in the cytoplasm, acts like an uncoupler in disrupting cytoplasmic ion balance, and triggers multiple effects, including osmotic stress and futile respiration

Situation analysis for delivering integrated comprehensive sexual and reproductive health services in humanitarian crisis condition for Rohingya refugees in Cox's Bazar, Bangladesh: protocol for a mixed-method study

INTRODUCTION:Rohingya diaspora are one of the most vulnerable groups seeking refuge in camps of Cox's Bazar, Bangladesh, arising an acute humanitarian crisis. More than half of the Rohingya refugees are women and adolescent girls requiring quality sexual and reproductive health (SRH) services. Minimum initial service package of SRH are being rendered in the refugee camps; however, WHO is aiming to provide integrated comprehensive SRH services to meet the unmet needs of this most vulnerable group. For sustainable and successful implementation of such comprehensive SRH service packages, a critical first step is to undertake a situation analysis and understand the current dimensions and capture the lessons learnt on their SRH-specific needs and implementation challenges. This situation analysis is pertinent in current humanitarian condition and will provide an overview of the needs, availability and delivery of SRH services for adolescent girls and women, barriers in accessing and providing those services in Rohingya refugee camps in Cox's Bazar, Bangladesh, and similar humanitarian contexts. METHODS AND ANALYSIS:A concurrent mixed-methods design will be used in this study. A community-based household survey coupled with facility assessments as well as qualitative in-depth interviews, key informant interviews and focus group discussions will be conducted with community people of Rohingya refugee camps and relevant stakeholders providing SRH services to Rohingya population in Cox's Bazar, Bangladesh. Survey data will be analysed using univariate, bivariate and multivariable regression statistics. Descriptive analysis will be done for facility assessment and thematic analysis will be conducted with qualitative data. ETHICS AND DISSEMINATION:Ethical approval from Institutional Review Board of BRAC James P Grant School of Public Health (2018-017-IR) has been obtained. Findings from this research will be disseminated through presentations in local, national and international conferences, workshops, peer-reviewed publications, policy briefs and interactive project report