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Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections.

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 ?g/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 ?pyk::Erm(R)) that lacks PK activity confirmed that bactericidal activity of 10d was PK-dependant.

SUBMITTER: Kumar NS

PROVIDER: S-EPMC6108325 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections.

Kumar Nag S NS Dullaghan Edie M EM Finlay B Brett BB Gong Huansheng H Reiner Neil E NE Jon Paul Selvam J J Thorson Lisa M LM Campbell Sara S Vitko Nicholas N Richardson Anthony R AR Zoraghi Roya R Young Robert N RN

Bioorganic & medicinal chemistry 20140124 5

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 res ...[more]

PMID: 24508307

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Project description:BackgroundBloodstream infections due to Staphylococcus aureus cause significant patient morbidity and mortality worldwide. Of major concern is the emergence and spread of methicillin-resistant S. aureus (MRSA) in bloodstream infections, which are associated with therapeutic failure and increased mortality.MethodsWe generated high quality draft genomes from 323 S. aureus blood culture isolates from patients diagnosed with bloodstream infection at the Dartmouth-Hitchcock Medical Center, New Hampshire, USA in 2010-2018.ResultsIn silico detection of antimicrobial resistance genes revealed that 133/323 isolates (41.18%) carry horizontally acquired genes conferring resistance to at least three antimicrobial classes, with resistance determinants for aminoglycosides, beta-lactams and macrolides being the most prevalent. The most common resistance genes were blaZ and mecA, which were found in 262/323 (81.11%) and 104/323 (32.20%) isolates, respectively. Majority of the MRSA (102/105 isolates or 97.14%) identified using in vitro screening were related to two clonal complexes (CC) 5 and 8. The two CCs emerged in the New Hampshire population at separate times. We estimated that the time to the most recent common ancestor of CC5 was 1973 (95% highest posterior density (HPD) intervals: 1966-1979) and 1946 for CC8 (95% HPD intervals: 1924-1959). The effective population size of CC8 increased until the late 1960s when it started to level off until late 2000s. The levelling off of CC8 in 1968 coincided with the acquisition of SCCmec Type IV in majority of the strains. The plateau in CC8 also coincided with the acceleration in the population growth of CC5 carrying SCCmec Type II in the early 1970s, which eventually leveled off in the early 1990s. Lastly, we found evidence for frequent recombination in the two clones during their recent clonal expansion, which has likely contributed to their success in the population.ConclusionsWe conclude that the S. aureus population was shaped mainly by the clonal expansion, recombination and co-dominance of two major MRSA clones in the last five decades in New Hampshire, USA. These results have important implications on the development of effective and robust strategies for intervention, control and treatment of life-threatening bloodstream infections.

Project description:ImportanceEstimating the US burden of methicillin-resistant Staphylococcus aureus (MRSA) infections is important for planning and tracking success of prevention strategies.ObjectiveTo describe updated national estimates and characteristics of health care- and community-associated invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in 2011.Design, setting, and participantsActive laboratory-based case finding identified MRSA cultures in 9 US metropolitan areas from 2005 through 2011. Invasive infections (MRSA cultured from normally sterile body sites) were classified as health care-associated community-onset (HACO) infections (cultured ≤ 3 days after admission and/or prior year dialysis, hospitalization, surgery, long-term care residence, or central vascular catheter presence ≤ 2 days before culture); hospital-onset infections (cultured >3 days after admission); or community-associated infections if no other criteria were met. National estimates were adjusted using US census and US Renal Data System data.Main outcomes and measuresNational estimates of invasive HACO, hospital-onset, and community-associated MRSA infections using US census and US Renal Data System data as the denominator.ResultsAn estimated 80,461 (95% CI, 69,515-93,914) invasive MRSA infections occurred nationally in 2011. Of these, 48,353 (95% CI, 40,195-58,642) were HACO infections; 14,156 (95% CI, 10,096-20,440) were hospital-onset infections; and 16,560 (95% CI, 12,806-21,811) were community-associated infections. Since 2005, adjusted national estimated incidence rates decreased among HACO infections by 27.7% and hospital-onset infections decreased by 54.2%; community-associated infections decreased by only 5.0%. Among recently hospitalized community-onset (nondialysis) infections, 64% occurred 3 months or less after discharge, and 32% of these were admitted from long-term care facilities.Conclusions and relevanceAn estimated 30,800 fewer invasive MRSA infections occurred in the United States in 2011 compared with 2005; in 2011 fewer infections occurred among patients during hospitalization than among persons in the community without recent health care exposures. Effective strategies for preventing infections outside acute care settings will have the greatest impact on further reducing invasive MRSA infections nationally.

Dataset Information

Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections.

Publications

Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections.

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