Discovery, synthesis and evaluation of a novel ketol-acid reductoisomerase inhibitor.

Discovery, synthesis and evaluation of a novel ketol-acid reductoisomerase inhibitor. Chemistry. 2020 Mar 21;: Authors: Bayaraa T, Kurz JL, Patel KM, Hussein WM, Bilyj JK, West NP, Schenk G, McGeary RP, Guddat LW Abstract Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis . Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis ( Mt ) KARI and identified two compounds that have K i values below 200 nM. In Mt cell susceptibility assays one of these compounds exhibited an IC 50 value of 0.8 μM. Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2 H -benzo[ b ][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56% identity with Mt KARI, NADPH and Mg 2+ yielded a structure to 1.72 Å resolution. However, only a hydrolyzed product of the inhibitor ( i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, we have identified 3-(methylsulfonyl)-2-oxopropanic acid is a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug le...
Source: Chemistry - Category: Chemistry Authors: Tags: Chemistry Source Type: research

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Dalton Trans., 2020, Accepted Manuscript DOI: 10.1039/D0DT01365J, PerspectiveLuiz Gonzaga Fran ça de França Lopes, Edinilton Muniz Carvalho, Eduardo Henrique Silva Sousa Medicinal inorganic chemists have provided many strategies to tackle a myriad of diseases, pushing forward the frontiers of pharmacology. As an example, the fight against tuberculosis (TB), an infectious bacterial... The content of this RSS Feed (c) The Royal Society of Chemistry
Source: RSC - Dalton Trans. latest articles - Category: Chemistry Authors: Source Type: research
Publication date: June 2020Source: Journal of Global Antimicrobial Resistance, Volume 21Author(s): Lebogang Kenaope, Hannetjie Ferreira, Faheem Seedat, Kennedy Otwombe, Neil A. Martinson, Ebrahim Variava
Source: Journal of Global Antimicrobial Resistance - Category: Infectious Diseases Source Type: research
In this study, we present three cases of testicular infarction and discuss their clinical characteristics, imaging features and clinical management. PATIENTS AND METHODS: Three adult males with prolonged epididymitis presented with chronic unilateral testicular pain, tenderness, and palpable swelling, including left varicocele in one case and hydrocele in the other two cases. Patient's symptoms were not relieved after antibiotic therapy. We analyzed the diagnosis, management, and outcome of these three cases of testicular infarction resulting from prolonged epididymitis. This includes the clinical characteristics, feat...
Source: Journal of X-Ray Science and Technology - Category: Radiology Tags: J Xray Sci Technol Source Type: research
This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free." Commentary on Recent Evidence for Cognitive Decline to Precede Amyloid Aggregation in Alzheimer's Disease I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
CONCLUSION: Despite a significant reduction in paediatric inpatient mortality in Malawi, infectious diseases remain the predominant cause. ABBREVIATIONS: ART: anti-retroviral therapy; Child PIP: Child Healthcare Problem Identification Programme; CCF: congestive cardiac failure; CNS: central nervous system; CoNS: coagulase-negative staphylococci; CSF: cerebrospinal fluid; DNA pcr: deoxyribonucleic acid polymerase chain reaction; ETAT: emergency triage assessment and treatment; LMIC: low- and middle-income countries; MDG: Millennium Development Goals; MRI: magnetic resonance imaging; MRSA: methicillin-resistant Staphyloc...
Source: Paediatrics and international child health - Category: Pediatrics Tags: Paediatr Int Child Health Source Type: research
150 years after Semmelweis advised fellow physicians to sanitize their hands to mitigate the effect of infections, the maintenance of hygiene is still a widespread problem in hospitals and the source of healthcare-associated infections. Now, technological solutions line up against microorganisms, bacteria, and fungi. Here are a few examples. 1 in 9 in-patients will die due to infection According to the US Center for Disease Control, studies show that on average, healthcare providers clean their hands less than half of the times they should. This significantly contributes to the spread of healthcare-associated infections (H...
Source: The Medical Futurist - Category: Information Technology Authors: Tags: Healthcare Design Medical Professionals Policy Makers clean digital digital health future HAI healthcare-associated infection hygiene Medicine robot robotics sensors technology trackers wearable Source Type: blogs
by Jonas I. Liechti, Gabriel E. Leventhal, Sebastian Bonhoeffer Intense use of antibiotics for the treatment of diseases such as tuberculosis, malaria,Staphylococcus aureus or gonorrhea has led to rapidly increasing population levels of drug resistance. This has generally necessitated a switch to new drugs and the discontinuation of older ones, after which resistance often only declines slowly or even persists indefinitely. These long-term effects are usually ascribed to low fitness costs of resistance in absence of the drug. Here we show that structure in the host population, in particular heterogeneity in number of cont...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research
Abstract Purpose of Review Well-established as a powerful tool for preventing disease, vaccines have immeasurably impacted health and disease epidemiology worldwide. In the era of rational vaccine design and ever-evolving technology, vaccine development and delivery is poised to improve the ability to target a range of new diseases and to improve disease prevention, in even the most remote communities worldwide. Recent Findings New vaccines against influenza, human papillomavirus and meningococcal diseases have focused on targeting an increased number of...
Source: Current Pediatrics Reports - Category: Pediatrics Source Type: research
This study aimed to assess bacteremias and malaria in children from urban and rural areas in Gabon. DNA extracts from blood samples of 410 febrile and 60 afebrile children were analyzed using quantitative polymerase chain reaction. Plasmodium spp. was the microorganism most frequently detected in febrile (78.8%, 323/410) and afebrile (13.3%, 8/60) children, (P
Source: The American Journal of Tropical Medicine and Hygiene - Category: Tropical Medicine Authors: Tags: Am J Trop Med Hyg Source Type: research
Conclusion Fevers other than malaria, such as dengue, pyelonephritis, rickettsioses and typhoid are common causes of fever during pregnancy in the Asian tropics. Further investigations of their impact in the community on maternal death, fetal loss, vertical transmission, low birth weight and preterm birth are needed.
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
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