Marine Drugs Macrolactins - Wiley Online Library

CHEMISTRY & BIODIVERSITY – Vol. 5 (2008)

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REVIEW Marine Drugs – Macrolactins Xiao-Ling Lu a ) b ), Qiang-Zhi Xu a ), Xiao-Yu Liu a ), Xin Cao c ), Kun-Yi Ni b ), Bing-Hua Jiao* a ) a

) Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, No. 800 Xiangyin Road, Shanghai 200433, P. R. China (phone: þ 86-21-65493936; fax: þ 86-21-65334344; e-mail: [email protected]) b ) Department of Analytical Chemistry, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, P. R. China c ) Department of Medicinal Chemistry, College of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, P. R. China

The increasing demands for new lead compounds in pharmaceutical and agrochemical industries have driven scientists to search for new bioactive natural products. Marine microorganisms are rich sources of novel, bioactive secondary metabolites, and have attracted much attention of chemists, pharmacologists, and molecular biologists. This mini-review mainly focuses on macrolactins, a group of 24-membered lactone marine natural products, aiming at giving an overview on their sources, structures, biological activities, as well as their potential medical applications.

Introduction. – The traditional sources of bioactive compounds were terrestrial plants and microorganisms which could be easily obtained and readily explored. In comparison, the ocean source was scarcely studied. However, since the 1970s, as a consequence of advanced technology, ocean has become an attracting area in drug development for the structural diversities and pharmacological potentials which were presented by the novel scaffold of the molecules isolated from this environment [1]. Marine natural products have been one of the main subjects of chemical and pharmacological interests for several decades, leading to an important library of diversely bioactive compounds [2]. Marine microorganisms, which are taxonomically diverse and genetically special, have powerful potential in producing novel bioactive substances [3]. Macrolactins are a group of 24-membered lactones, with potent antibacterial or other activities, most of which were derived from the second metabolites of the marine microorganisms, while several of them were also produced by some soil microorganisms as well. There were a total of 18 isolated macrolactins that have been reported including the recent discoveries of our group, since the first of them, macrolactin A had been isolated in 1989. All macrolactins contain three separate diene structure elements, which were named as macrolactins A – N, 7-O-succinylmacrolactin A, 7-O-succinylmacrolactin F, and 7-O-malonylmacrolactin A, respectively. Here, all macrolactins, as well as their sources, structures, and the biological activities were reviewed. Macrolactins A – F. – Macrolactins A – F were previously reported by Gustafson et al. as 24-membered ring lactones isolated from an unclassifiable deep-sea bacterium B 2008 Verlag Helvetica Chimica Acta AG, ZErich

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[4]. Macrolactin A showed selective antibacterial activities, cytotoxicity against B16-F10 murine melanoma cancer cells, and antiviral activities against Herpes simplex and HIV. Macrolactin A was also isolated from a culture broth of Actinomadura sp. as a neuronal-cell-protecting substance by Kim et al. [5], and from Bacillus sp. sunhua of the soil of a potato-cultivating area [6]. Macrolactin A and macrolactin F were both produced by a soil Streptomyces species, which were squalene synthase inhibitors [7].


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Kinetic results for macrolactins A and F showed that they were noncompetitive inhibitors of rat liver squalene synthase with IC50 values of 1.66 and 1.53 mm, respectively. In spite of their interesting activities, however, there were no further studies on the activities of macrolactins because of the lack of natural material. This led to the total synthesis of macrolactin A [8 – 17] based on its estimated three-dimensional architecture [18]. In the meanwhile, macrolactin E was also chemically synthesized [16]. Because of the various biological activities of macrolactin A, reseachers tried to study further its action mechanism. Although cloning of the macrolactin A biosynthetic genes has not been reported, its chemical structure suggests that it is assembled by a modular polyketide synthases system (PKS system) like macrolides. The PKS system is a primary and important element of the biosynthetics of macrolides. Macrolactins structurally belong to the macrolides, so it is assumed that macrolactins may assemble by PKS like macrolides [19]. The macrolactone rings of macrolides are formed via cyclization of polyketide chains assembled by the PKS type-I enzymes that perform repetitive decarboxylative condensations of carboxylic acids with an activated carboxylic acid starter unit [20]. On the basis of the PKS system, Zotchev et al. [19] used PASS/PharmaExpert software to speculate on the antibacterial activity of macrolactins that it could be due to the inhibition of the H þ -transporting two-sector ATPase, which is essential for viability of bacterial cells. Antiviral activities of macrolactins could probably be attributed to the phosphatase inhibitory activity, and certain protein phosphatases were involved in regulation of HIV transcription. They

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also predicted that macrolactins may possess some other activities, such as antimetastatic, acylcarnitine hydrolase inhibition, antiseborrhic, cardiovascular analeptic, and microtubule stabilization. Macrolactins G – M. – Macrolactins G – M, isolated from a culture broth of Bacillus sp. PP19-H3, were reported by Nagao et al. in 2001 [21]. These macrolactins include a 22-membered ring or bicyclic lactone in addition to their geometric isomers of macrolactin A and F. The antibacterial activities of these macrolactins were relatively weak. These macrolactins were more effective against Staphylococcus aureus than Bacillus subtilis, but could not inhibit Escherichia coli and Salinivibrio costicola. On the basis of the antibacterial activity data, Nagao et al. suggested that the OH group at C(15) may play an important role in antibacterial activity of macrolactins. Macrolactin N. – Macrolactin N was a new peptide deformylase inhibitor produced by Bacillus subtilis [22]. This compound is the first macrolactin dehydroxylated at C(13), which showed stronger antibacterial activity against E. coli than S. aureus and B. subtilis. It inhibited bacterial growth against E. coli with a MIC value of 100 mg/ml, while it was relatively weaker in inhibition of S. aureus and B. subtilis MIC50 values of 100 and 100 mg/ml, respectively. Macrolactin N inhibited S. aureus peptide deformylase (PDF) in a dose-dependent manner with an IC50 value of 7.5 mm. 7-O-Succinylmacrolactin A and 7-O-Succinylmacrolactin F. – 7-O-Succinylmacrolactin A and 7-O-succinylmacrolactin F, together with macrolactin F, were isolated from the AcOEt extract of a marine Bacillus sp. Sc026 culture broth [23]. These two new compounds showed optical rotations similar to those of their parent macrolactins A and F, respectively. Therefore, it can be assumed that both new macrolactins have the same configurations as their respective parent molecules. Regarding their antibacterial activities, 7-O-succinylmacrolactin F was tested at 100 mg/disk, while 7-O-succinylmacrolactin A was tested at 50 mg/disk. The inhibition zones of 7-O-succinylmacrolactin F and 7-O-succinylmacrolactin A against Bacillus subtilis were 9 and 10 mm, and against Staphylococcus aureus 8 and 24 mm, respectively. 7-O-Malonylmacrolactin A. – 7-O-Malonylmacrolactin A (MMA) was a new antibiotic compound which was produced by a Bacillus subtilis soil isolate [24] [25]. MMA was a bacteriostatic antibiotic that inhibited 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 they exhibited multiple asymmetric initiation points of septum formation, indicating that MMA may inhibit the cell-division function. Though macrolactins have been known since the late 1980s, there is only one report on their action mode. Magally et al. [24] suggested that MMA inhibited one or more stages in cell division, and interfered cell-wall synthesis. Because pseudomulticellular clusters are unable to produce daughter cells, as a consequence, it was assumed that MMA should have a reduced ability to disseminate, and should, therefore, be less virulent. They also observed the same phenomenon in 7-O-succinylmacrolactin A. On


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the basis of the experimental data, 7-O-succinylmacrolactin A and MMA showed superior antibacterial activity and lower cytotoxicity in comparison with macrolactin A, indicating an important role of the residue at C(7) in the biological activities of these compounds. MMA was the most active compound against selected reference microorganisms and clinical multiresistants in the macrolactin family [26]. Furthermore, it is less cytotoxic than macrolactin A itself, and its known derivatives render the new compound attractive for pharmaceutical application. Macrolactin S. – In 2006, our group isolated a new macrolactin, named macrolactin S, from a marine Bacillus subtilis [27]. Macrolactin S inhibited bacterial growth against E. coli with a MIC value of 0.2 mg/ml, while it was relatively weaker in inhibiting the bacterial growth of S. aureus and B. subtilis with MIC values of 0.7 and 100 mg/ml, respectively. Its chemical structure suggested that it is also assembled by a modular PKS system. KS Domains cloned from our marine Bacillus strain showed 98% identity to the known pks2 gene cluster in environmental strain Bacillus amyloliquefaciens FZB42. The result showed that the pks2 gene cluster may play an important role in the biosynthesis of macrolactins. Data presented in this study showed that the PCR method using degenerate primer to isolate the secondary-metabolites biosynthesis gene fragments from the environmental samples and strains was practically effective. Further evaluation of this compound is under way. Outlook. – Among all macrolactins isolated, the majority was marine-derived. Most macrolactins show antibacterial activities. Besides, macrolactin A possesses various bioactivities. The action mechanisms of these compounds are still under research. The structures of macrolactins suggest that they may be assembled by a modular PKS system. In the near future, the action mechanisms and biosynthesis of the macrolactins may become an attractive field. This work was supported by Shanghai Outstanding Field Leaders Program (05XD1423) to B.-H. J., National Hi-Tech R&D Program to B.-H. J. (2007AA091501), X.-Y. L. (2006AA09Z416), and Q.-Z. X. (2006AA09Z425). REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

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