Total Synthesis of (−)-Macrolactin A

Smith, Iii and Amos B.; Ott, Gregory R.

doi:10.1021/ja963543a

Cited by 124 publications

(65 citation statements)

References 22 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

127

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

127

115

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“…Selective cleavage of the 4,6-O-benzylidene group [25] with ethanethiol in the presence of TsOH as catalyst in dichloromethane, followed by acetylation gave the desired compound 9. Removal of the O-silyl group with tetrabutyl-A C H T U N G T R E N N U N G ammonium fluoride (TBAF) [26] under acidic conditions and then reaction with trichloroacetonitrile in the presence of 1,8-diazabicyclohexylcarbodiimide (DBU) [27] as base furnished the desired building block 4 in good yield.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Monomeric and Dimeric Repeating Units of the Zwitterionic Type 1 Capsular Polysaccharide from Streptococcus pneumoniae

Cui

Lipiński

et al. 2010

Chemistry A European J

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Zwitterionic polysaccharides (ZPSs) from Bacteroides fragilis and Streptococcus pneumoniae display unique T-cell activities. The first synthesis of a hexasaccharide representing two repeating units of the zwitterionic capsular polysaccharide from S. pneumoniae type 1 (Sp1) is reported. Key elements of the approach are stereoselective construction of 1,4-cis-alpha-galactose linkages based on a reactive trichloroacetimidate donor that incorporates a 6-O-acetyl group, which may contribute to the high alpha selectivity in glycosylation. After assembly of the fully protected hexasaccharide from five monosaccharide synthons 2-4, 24 and 25, selective deprotection of the primary hydroxyl groups of the four galactose residues followed by oxidation to the corresponding uronic acids provides hexasaccharide 19. The trisaccharide counterpart 1 was synthesized in similar fashion from three synthons, 2-4. This approach employed both conventional and dehydrative glycosylation methodologies and avoids the use of poorly reactive uronic acid derived glycosyl donors and acceptors.

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“…The mixture was concentrated to a residue, using toluene as an azeotrope, that was purified by flash column chromatography (hexane/EtOAc, 1:1) to give the title compound 8 (84 mg, 93%) as a colorless syrup. (c) Glacial acetic acid (143 µL, 2.50 mmol) and TBAF (1  in THF; 1.25 mL, 1.25 mmol) [23] were added sequentially to a solution of compound 7 (139 mg, 0.250 mmol) in THF (2 mL). After stirring for 1 day at room temp., TBAF (1  in THF; 0.63 mL, 2.5 molar equiv.)…”

Section: Methyl 467-tri-o-acetyl-2-o-benzyl-l-glycero-α-d-manno-hepmentioning

confidence: 99%

“…Although de-O-silylation of the 3-O-TBDMS ether 7 did not reach completion when using either I 2 /MeOH or tetrabutylammonium fluoride (TBAF) buffered with acetic acid (AcOH), [23] the TBDMS group was removed by treating 7 for 15 min in TFA/water (9:1, v/v) [24] to give 8 in 93% yield. Compound 8 was also prepared from 3 in 91% yield by sequentially carrying out the silylation, acetylation, and subsequent hydrolysis steps without isolating 4 and 5.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a 2,3‐Di‐O‐substituted Heptose Structure by Regioselective 3‐O‐Silylation of a 2‐O‐Substituted Heptose Derivative

et al. 2004

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A 3,4‐diol derivative of 2‐O‐benzyl (Bn) heptose (Hep), methyl 6,7‐di‐O‐acetyl‐2‐O‐benzyl‐L‐glycero‐α‐D‐manno‐heptopyranoside (3), was treated with both triethylsilyl (TES) and tert‐butyldimethylsilyl (TBDMS) chlorides to regioselectively form the 3‐O‐silyl ethers 4 and 6, respectively. To examine whether silylation of the 3,4‐diol of a 2‐O‐substituted disaccharide also gives the corresponding 3‐O‐silylated disaccharide, we synthesized α‐GlcN3‐(1⇄2)‐Hep 11a by coupling a Hep 2‐OH acceptor 9 with a GlcN3 trichloroacetimidate 10. As expected from the results obtained using the 2‐O‐Bn Hep 3, treatment of α‐GlcN3‐(1⇄2)‐Hep‐3,4‐diol 14 with TESCl followed by acetylation gave only the 3‐O‐TES 15. Compound 14 was converted into the 3‐OH acceptor 16 by silylation/acetylation — without isolating 15 — and subsequent acid hydrolysis. By coupling the disaccharide 3‐OH acceptor 16 with per‐O‐benzylated β‐lactosyl trichloroacetimidate 17, we obtained the desired 2,3‐branched tetrasaccharide, α‐Lac‐(1⇄3)‐[α‐GlcN3‐(1⇄2)]‐Hep 18a. Hydrogenation of 18a, followed by N‐acetylation, gave α‐Lac‐(1⇄3)‐[α‐GlcNAc‐(1⇄2)]‐Hep 22. Thus, we synthesized the 2,3‐dibranched Hep by utilizing the 2‐O‐substituted Hep. This regioselective O‐3‐silylation of the 2‐O‐substituted Hep provides an intermediate that can be utilized for the synthesis of not only 2,3‐ and 3,4‐dibranched Hep but also the 2,3,4‐tribranched Hep structures present in lipooligo‐ and lipopolysaccharides produced by pathogenic Gram‐negative bacteria. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

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Total Synthesis of (−)-Macrolactin A

Cited by 124 publications

References 22 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

Synthesis of Monomeric and Dimeric Repeating Units of the Zwitterionic Type 1 Capsular Polysaccharide from Streptococcus pneumoniae

Synthesis of a 2,3‐Di‐O‐substituted Heptose Structure by Regioselective 3‐O‐Silylation of a 2‐O‐Substituted Heptose Derivative

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