Stereocontrolled Synthesis of (−)-Macrolactin A

Marino, Joseph P.; McClure, Michael S.; Holub, David P.; Comasseto, J. V.; Tucci, Fábio C.

doi:10.1021/ja017177t

Cited by 177 publications

(74 citation statements)

References 40 publications

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“…(10,16,18,23). Six macrolactins were first described in 1989 by Gustafson (22,33,34). Macrolactins are considered to be potent antiviral and cytotoxic agents that also have antibacterial activity (10,16).…”

Section: Discussionmentioning

confidence: 99%

7- O -Malonyl Macrolactin A, a New Macrolactin Antibiotic from Bacillus subtilis Active against Methicillin-Resistant Staphylococcus aureus , Vancomycin-Resistant Enterococci, and a Small-Colony Variant of Burkholderia cepacia

Romero-Tabarez

Jansen

Sylla

et al. 2006

Antimicrob Agents Chemother

128

115

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We report here the discovery, isolation, and chemical and preliminary biological characterization of a new antibiotic compound, 7-O-malonyl macrolactin A (MMA), produced by a Bacillus subtilis soil isolate. MMA is a bacteriostatic antibiotic that inhibits a number of multidrug-resistant gram-positive bacterial pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and a small-colony variant of Burkholderia cepacia. MMA-treated staphylococci and enterococci were pseudomulticellular and exhibited multiple asymmetric initiation points of septum formation, indicating that MMA may inhibit a cell division function.The spread of resistance to antibiotics undermines the therapeutic utility of anti-infective drugs in current clinical use (1). For example, Staphylococcus aureus, a major cause of community-and hospital-acquired infections, has developed resistance to most classes of antibiotics. Methicillin-resistant S. aureus (MRSA) strains appeared in the hospital environment after introduction of the semisynthetic penicillin methicillin, leaving vancomycin as the last line of defense for MRSA treatment (7). S. aureus organisms intermediately susceptible to vancomycin were first isolated in 1997 in Japan (15) and later in other countries (8). With the recent appearance of vancomycin-resistant clinical isolates (32,36,38), no antibiotic class is effective against multiresistant S. aureus infections. The increase in vancomycin-resistant enterococci (VRE), important agents of nosocomial infections, is another cause of great concern (2,3,19,27). Therapy options for multiresistant gramnegative opportunistic bacterial pathogens are also diminishing. Such bacteria, like Pseudomonas aeruginosa and Burkholderia cepacia (6), are common environmental organisms and opportunistic pathogens having the capacity to infect essentially all tissues of patients with compromised host defenses (21).Compounding the problem of genetically determined transmissible antibiotic resistance is the development of phenotypically resistant, often slow-growing, forms in chronic bacterial infections. These may take the form of biofilm microbes or small-colony variants (SCV) (12; reviewed in reference 14), are known to include both gram-positive and gram-negative pathogens, and are usually associated with a worsening of the disease prognosis.Thus, new antibiotics and therapy options are urgently needed to improve the management of bacterial infections (29, 35), and a major challenge is to find drugs that act against SCV and/or bacteria growing in biofilms.In this study, we report the discovery and preliminary characterization of 7-O-malonyl macrolactin A (MMA), a new antibiotic having bacteriostatic activity against clinical strains of MRSA, VRE, and a SCV of Burkholderia cepacia. The parental wild-type (WT) and SCV pairs of P. aeruginosa and B. cepacia, as well as Stenotrophomonas maltophilia strain 1124, were isolated from cystic fibrosis patients in the Department of Medical Microbiology at the Medical School...

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Section: Discussionmentioning

confidence: 99%

7- O -Malonyl Macrolactin A, a New Macrolactin Antibiotic from Bacillus subtilis Active against Methicillin-Resistant Staphylococcus aureus , Vancomycin-Resistant Enterococci, and a Small-Colony Variant of Burkholderia cepacia

Romero-Tabarez

Jansen

Sylla

et al. 2006

Antimicrob Agents Chemother

128

115

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“…The keto azide 34 (0.66 g, 2.6 mmol) was dissolved in 26 mL of THF and treated with 1-(tert-butyldimethylsilyloxy)pent-2-ene-4-ynyl lithium 22 (2.6 mmol) at room temperature. After 20 min, the dark solution was treated with 15 mL of aqueous NH 4 Cl and the mixture was extracted with 50 mL of Et 2 O.…”

Section: Tetrasubstituted Allene Substrate 38cmentioning

confidence: 99%

Allenyl Azide Cycloaddition Chemistry: Exploration of the Scope and Mechanism of Cyclopentennelated Dihydropyrrole Synthesis through Azatrimethylenemethane Intermediates

et al. 2008

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Detailed studies of the thermal conversion of 1-azidohepta-3,4,6-trienes into cyclopentennelated dihydropyrroles are presented. High levels of diastereoselectivity and regioselectivity are documented. A mechanistic proposal that accounts for all of the diverse results is developed through the use of density functional calculations. These calculations provide support for the intervention of unexpected mechanistic subtleties, such as the planarity of an azatrimethylenemethane diyl intermediate and an apparent Woodward-Hoffmann-type electrocyclization of a five-atom diyl array.

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“…[9][10][11][12] In view of this interest in the organic compounds of this element, analytical methods for their rapid identification are welcome. Nuclear magnetic resonance (NMR) spectroscopy in nowadays is the routine technique of choice for this end.…”

Section: Introductionmentioning

confidence: 99%

Computer-aided prediction of 125Te and 13C NMR chemical shifts of diorgano tellurides

Emerenciano

Diego

Ferreira

et al. 2007

J. Braz. Chem. Soc.

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Esse trabalho descreve um método para previsão dos deslocamentos químicos de RMN de 125 Te e 13 C de diorgano-teluretos baseado em uma abordagem tridimensional. Para tanto, 150 substâncias foram selecionadas da literatura e tiveram suas respectivas geometrias otimizadas através do método semi-empírico PM3. A partir desses dados, as estruturas foram codificadas através do programa FOCOS, que descreve o ambiente químico de cada átomo presente na estrutura, num total de 1411 focos para as substâncias. O método descrito foi testado com dez diorgano teluretos não inseridos na base de dados e mostrou uma exatidão maior na previsão de deslocamentos químicos de RMN de 125 Te e 13 C do que os dados previstos por um programa comercial. Os dados e os parâmetros estatísticos obtidos nesse estudo demonstram que o método aplicado foi capaz de prever com sucesso os deslocamentos químicos de RMN de 125 Te e 13 C dos diorgano teluretos.This work describes a method to predict the 125 Te and 13 C NMR chemical shifts of diorgano tellurides based in a three-dimensional approach. For that, a collection of 150 compounds were selected from the literature and had their geometry optimized using the PM3 semi-empirical method. From this data, the structures were coded by the FOCOS program which described the chemical environment for each atom present in the structure, totalizing 1411 focos for the substances. The method developed was tested with ten diorgano tellurides not inserted in the database showing a higher accuracy in the prediction of 125 Te and 13 C NMR chemical shifts than those predicted by the commercial program. The chemical shifts and the statistical parameters obtained in this work demonstrate that the method applied was able to predict successfully the 13 C and 125 Te NMR chemical shifts of the diorgano tellurides.

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Stereocontrolled Synthesis of (−)-Macrolactin A

Cited by 177 publications

References 40 publications

7- O -Malonyl Macrolactin A, a New Macrolactin Antibiotic from Bacillus subtilis Active against Methicillin-Resistant Staphylococcus aureus , Vancomycin-Resistant Enterococci, and a Small-Colony Variant of Burkholderia cepacia

7- O -Malonyl Macrolactin A, a New Macrolactin Antibiotic from Bacillus subtilis Active against Methicillin-Resistant Staphylococcus aureus , Vancomycin-Resistant Enterococci, and a Small-Colony Variant of Burkholderia cepacia

Allenyl Azide Cycloaddition Chemistry: Exploration of the Scope and Mechanism of Cyclopentennelated Dihydropyrrole Synthesis through Azatrimethylenemethane Intermediates

Computer-aided prediction of 125Te and 13C NMR chemical shifts of diorgano tellurides

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