Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the β-Ketoacyl-ACP Synthase mtFabH

Background Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration. Methodology/Principal Findings Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylateinhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. Conclusions/Significance These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents

“Ten Commandments” for the Appropriate use of Antibiotics by the Practicing Physician in an Outpatient Setting

A multi-national working group on antibiotic stewardship, from the International Society of Chemotherapy, put together ten recommendations to physicians prescribing antibiotics to outpatients. These recommendations are: (1) use antibiotics only when needed; teach the patient how to manage symptoms of non-bacterial infections; (2) select the adequate ATB; precise targeting is better than shotgun therapy; (3) consider pharmacokinetics and pharmacodynamics when selecting an ATB; use the shortest ATB course that has proven clinical efficacy; (4) encourage patients’ compliance; (5) use antibiotic combinations only in specific situations; (6) avoid low quality and sub-standard drugs; prevent prescription changes at the drugstore; (7) discourage self-prescription; (8) follow only evidence-based guidelines; beware those sponsored by drug companies; (9) rely (rationally) upon the clinical microbiology lab; and (10) prescribe ATB empirically – but intelligently; know local susceptibility trends, and also surveillance limitations

Antifungal Effect of Henna against Candida albicans Adhered to Acrylic Resin as a Possible Method for Prevention of Denture Stomatitis

Denture stomatitis is a very common disease affecting the oral mucosa of denture wearers. The aim of this study was to measure the antifungal effect of henna against Candida albicans adhered to acrylic resin as a possible method for prevention of denture stomatitis. One-hundred-eighty acrylic plates were prepared of heat-cured acrylic denture resin. The specimens were divided into six groups of 30 samples each. The first group was only polymer and monomer following the conventional manufacturer instruction for processing complete dentures. The other five groups were processed by adding different concentration of Yamani henna powder (Harazi) to the polymer in a concentration of henna: polymer 1%, 2.5%, 5%, 7.5% and 10%, respectively. Samples were incubated in artificial saliva rich with Candida albicans at 37 °C, and the effect of henna on Candida albicans was evaluated in two different methods: semi-quantitative slide count and a culture-based quantitative assay (quantitative). Variation in the number of live Candida was observed with the increase in the concentration of Yamani henna powder. It was observed that the variation in live Candida, between control group and group B (concentration of Yamani henna powder was 1%), was statistically significant with a p-value of 0.0001. Similarly, variations in live Candida were significant, when the concentration of powder was 7.5% or 10% in contrast with control group and p-values were 0.0001 and 0.001 respectively. Adding henna to acrylic resin denture could be effective in controlling Candida albicans proliferation on the denture surface; however, its effects on the physical properties of acrylic resin denture need further studies

Clinical and Microbiological Characteristics of Candidemia Cases in Saudi Arabia

Wala Alkhalifa,1 Hassan Alhawaj,1 Aisha Alamri,2 Fatimah Alturki,1 Mohammed Alshahrani,3 Amani Alnimr1 1Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 2Department of Clinical Laboratory Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia; 3Emergency and Critical Care Department, King Fahad Hospital of the University - Imam Abdulrahman Bin Faisal University, Dammam, Saudi ArabiaCorrespondence: Wala Alkhalifa, 2722 Al Jouri Street, Saihat, Saudi Arabia, Tel +966 551873892, Email [email protected]: Candidemia and antifungal resistance are major healthcare challenges. The aim of this study is to describe the frequency of candidemia cases, distribution of Candida spp., and the associated risk factors for mortality in an academic institution in Saudi Arabia over an 18-month period. We also evaluated the susceptibility patterns of Candida blood isolates.Methods: Candidemia cases were collected from King Fahad Hospital of the University over the period between July 1st, 2020 through December 31st, 2021. They were prospectively reviewed for the preceding risk factors and antifungal (AF) susceptibility, testing results to fluconazole (FL), voriconazole (VO), itraconazole (IT), posaconazole (PO), caspofungin (CASP), anidulafungin (AND), micafungin (MYC), flucytosine (FLC) and amphotericin B (AMPB) using a broth microdilution kit (Sensititre™ YeastOne).Results: A total of 48 candidemia isolates were included that were isolated from 43 patients. The median age of cases was 62 ± 23.3 years (60.4% males and 83% ICU patients). Independent risk factors for mortality at 30 days in candidemia patients were age, COVID-19 co-infection, and use of tocilizumab. The most commonly isolated species were C. glabrata and C. parapsilosis (22.9% each) followed by C. albicans (18.75%). AF resistance for ≥ 1 antifungal was detected in 39.3% of 33 cases tested, with no cross-resistance identified. Resistance rates for each AF were as follows: FL (18%), VO (6%), IT (6%), PO (9%) and AMPB (3%). No resistance was seen for echinocandins apart from one C. krusei strain showing an intermediate result for CASP.Conclusion: The study showed an overall high rate of non-albicans Candida, with the predominance of C. parapsilosis and C. glabrata, representing a therapeutic challenge. AF resistance rate was high which emphasizes the importance of continuing surveillance and providing accurate and reliable tools in the laboratories for rapid speciation and susceptibility testing.Keywords: Candida, candidemia, invasive candidiasis, risk factors, epidemiology, antifungal susceptibility testin

Microbiological trends and mortality risk factors of central line-associated bloodstream infections in an academic medical center 2015–2020

Abstract Background Despite tremendous efforts to prevent central line-associated bloodstream infections, they still remain life-threatening complications among hospitalized patients with significant morbidity and mortality worldwide. The emerging antibiotic-resistant bacteria and other risk factors, including patient comorbidities, complicate patient management. Methods A single-center retrospective observational study was conducted at King Fahad Hospital of the University, Eastern Province, Saudi Arabia. Hospitalized patients with confirmed central line-associated bloodstream infections between January 2015 and December 2020 were included. The primary objectives were to investigate the trends in antibiotic susceptibility patterns of the causative agents, coexisting comorbid conditions, and other risk factors associated with mortality. Results A total of 214 patients with confirmed central line-associated bloodstream infections were included (CLABSI). The overall 30-day mortality rate was 33.6%. The infection rates per 1000 central line days for medical, surgical, and pediatric intensive care units were 4.97, 2.99, and 4.56 per 1000 CL days, respectively. The overall microbiological trends showed a predominance of Gram-negative agents, a steady increase of fungal CLABSI up to 24.0% in 2020, and a high prevalence of multidrug resistance up to 47% of bacterial CLABSI. In addition, the study indicates a significant negative surviving correlation with diabetes mellitus, cardiovascular disease, lung disease, chronic kidney disease, and the presence of ≥ 3 comorbidities (P < 0.05). Conclusion The microbiological trends of the study population demonstrated a steady increase of CLABSI caused by Candida spp. with a predominance of Gram-negative pathogens. Stratifying the patients according to relevant mortality risk factors, including patient comorbidities, will help reduce CLABSI rates and improve patient outcomes

Synthesis and Biological Evaluation of Purpurealidin E-Derived Marine Sponge Metabolites: Aplysamine-2, Aplyzanzine A, Suberedamines A and B

Five purpurealidin-derived marine secondary sponge metabolies have been synthesized through the carbodiimide coupling of an appropriate bromotyrosine unit. The structure elucidations have been confirmed through direct comparison with spectroscopic data of isolated natural products. Aplyzanzine A has been shown to be the most active product against a broad bacterial and fungal screen, demonstrating MIC values 2 to 4 times lower than the other metabolites in this study. Compounds 2, 3, 4a, and 5-7 exhibit a modest inhibition against slow growing mycobacteria (MIC 25-50 μg/mL), including Mycobacterium tuberculosis. iso-Anomoian A and suberedamine B showed antitumor activity in the NCI-DTP60 cell line screen at single-digit micromolar concentrations, with iso-anomoian A inhibiting 53 cell lines. These molecules present novel scaffolds for further optimization. New value: Five purpurealidin-derived marine secondary sponge metabolies have been synthesized through the carbodiimide coupling of an appropriate bromotyrosine unit. The structure elucidations have been confirmed through direct comparison with spectroscopic data of isolated natural products. Aplyzanzine A has been shown to be the most active product against a broad bacterial and fungal screen, demonstrating MIC values 2 to 4 times lower than the other metabolites in this study. Compounds 2, 3, 4a, and 5-7 exhibit a modest inhibition against slow growing mycobacteria (MIC 25-50 μg/mL), including Mycobacterium tuberculosis. iso-Anomoian A and suberedamine B showed antitumor activity in the NCI-DTP60 cell line screen at single-digit micromolar concentrations, with iso-anomoian A inhibiting 53 cell lines. These molecules present novel scaffolds for further optimization