ArticleBioorganic & medicinal chemistry2014
Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections.
Article in Bioorganic & medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- A Systematic Review of Recently Reported Marine Derived Natural Product Kinase Inhibitors.Marine drugs · 2019Pooled it
- Ultrasonic-Assisted Synthesis of Heterocyclic Curcumin Analogs as Antidiabetic, Antibacterial, and Antioxidant Agents Combined with in vitro and in silico Studies.Advances and applications in bioinformatics and chemistry : AABC · 2023Article
- Toward practical quantum embedding simulation of realistic chemical systems on near-term quantum computers.Chemical science · 2022Article
- Identification of the antibacterial mechanism of cryptotanshinone on methicillin-resistant Staphylococcus aureus using bioinformatics analysis.Scientific reports · 2021Article
- Ribosome-Amplified Metabolism, RAMBO, Measured by NMR Spectroscopy.Biochemistry · 2021Article
- Lack of nutritional immunity in diabetic skin infections promotesScience advances · 2020Article
- Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening.Microorganisms · 2020Article
- The Manganese-Dependent Pyruvate Kinase PykM Is Required for Wild-Type Glucose Utilization by Brucella abortus 2308 and Its Virulence in C57BL/6 Mice.Journal of bacteriology · 2018Article
- Amino Acid Catabolism inmBio · 2017Article
- Dragmacidin G, a Bioactive Bis-Indole Alkaloid from a Deep-Water Sponge of the Genus Spongosorites.Marine drugs · 2017Article
- Article
- Recent Advances in Drug Discovery from South African Marine Invertebrates.Marine drugs · 2015Review
- Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus.mBio · 2015Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
A novel series of bis-indoles derived from naturally occurring marine alkaloid 4 were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK is not only critical for bacterial survival which would make it a target for development of novel antibiotics, but it is reported to be one of the most highly connected 'hub proteins' in MRSA, and thus should be very sensitive to mutations and making it difficult for the bacteria to develop resistance. From the co-crystal structure of cis-3-4-dihydrohamacanthin B (4) bound to S. aureus PK we were able to identify the pharmacophore needed for activity. Consequently, we prepared simple direct linked bis-indoles such as 10b that have similar anti-MRSA activity as compound 4. Structure-activity relationship (SAR) studies were carried out on 10b and led us to discover more potent compounds such as 10c, 10d, 10k and 10 m with enzyme inhibiting activities in the low nanomolar range that effectively inhibited the bacteria growth in culture with minimum inhibitory concentrations (MIC) for MRSA as low as 0.5 μg/ml. Some potent PK inhibitors, such as 10b, exhibited attenuated antibacterial activity and were found to be substrates for an efflux mechanism in S. aureus. Studies comparing a wild type S. aureus with a construct (S. aureus LAC Δpyk::Erm(R)) that lacks PK activity confirmed that bactericidal activity of 10d was PK-dependant.
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