Abstract
Streptomyces ghanaensis ATCC14672 produces antibiotic moenomycin A (MmA), which possesses strong antibacterial activity. The genetic control of MmA biosynthesis has been recently elucidated; nevertheless, little is known about the roles of two pairs of genes, moeX5moeP5 and moeD5moeJ5, coding for ATP-dependent transporter systems. Here we report that both gene pairs form transcriptional units actively expressed during MmA production phase. Streptomyces ghanaensis mutants deficient in either (one) or both transporter systems are characterized by a decreased ability to produce moenomycins, and the ΔmoeP5moeX5 mutant exported less moenomycins. However, even the quadruple S. ghanaensis mutant (ΔmoeD5moeJ5 + ΔmoeX5moeP5) remains able to extrude significant amounts of moenomycin. Similar results were observed under conditions of heterologous expression of moe cluster. Transporter genes other than those located in moe cluster are likely to participate in moenomycin efflux.
Similar content being viewed by others
References
Alkhatib Z, Abts A, Mavaro A, Schmitt L, Smits SH (2012) Lantibiotics: how do producers become self-protected. J Biotechnol (epub ahead of print)
Blanc V, Salah-Bey K, Folcher M, Thompson CJ (1995) Molecular characterization and transcriptional analysis of a multidrug resistance gene cloned from the pristinamycin-producing organism, Streptomyces pristinaespiralis. Mol Microbiol 17:989–999
Bystrykh L, Fernandez-Moreno MA, Herrema JK, Malpartida F, Hopwood DA, Dijkhuizen L (1996) Production of actinorhodin-related “blue pigments” by Streptomyces coelicolor A3(2). J Bacteriol 178:2238–2244
Datsenko K, Wanner BL (2000) One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci USA 97:6640–6645
Gust B, Challis GL, Fowler K, Kieser T, Chater KF (2003) PCR-targeted Streptomyces gene replacement identifies a protein domain needed for biosynthesis of the sesquiterpene soil odor geosmin. Proc Natl Acad Sci USA 100:1541–1546
Huber PN (1979) Moenomycin and related phosphorus-containing antibiotics. In: Hahn FE (ed) Antibiotics. Springer, New York
Jain M, Cox JS (2005) Interaction between polyketide synthase and transporter suggests coupled synthesis and export of virulence lipid in Mycobacterium tuberculosis. PLoS Pathog 1:e2
Kieser T, Bibb MJ, Buttner MJ, Chater KF, Hopwood DA (2000) Practical Streptomyces genetics. John Innes Foundation, Norwich
Lee LF, Chen YJ, Kirby R, Chen C, Chen CW (2007) A multidrug efflux system is involved in colony growth in Streptomyces lividans. Microbiology 153:924–934
Liras P, Martin JF (2006) Gene clusters for beta-lactam antibiotics and control of their expression: why have clusters evolved, and from where did they originate? Int Microbiol 9:9–19
Luzhetskyy A, Ostash B, Fedorenko V (2001) Intergeneric conjugation Escherichia coli—Streptomyces globisporus 1912 with using of integrative plasmid pSET152 and its derivatives. Rus J Genet 37:340–1347
Makitrynskyy R, Rebets Y, Ostash B, Zaburannyi N, Rabyk M, Walker S, Fedorenko V (2010) Genetic factors that influence moenomycin production in streptomycetes. J Ind Microbiol Biotechnol 37:559–566
Malla S, Niraula NP, Liou K, Sohng JK (2010) Self-resistance mechanism in Streptomyces peucetius: overexpression of drrA, drrB and drrC for doxorubicin enhancement. Microbiol Res 165:259–267
Martín JF, Casqueiro J, Liras P (2005) Secretion systems for secondary metabolites: how producer cells send out messages of intercellular communication. Curr Opin Microbiol 8:282–293
Medema MH, Trefzer A, Kovalchuk A et al (2010) The sequence of a 1.8 Mb linear plasmid reveals a rich evolutionary reservoir of secondary metabolic pathways. Genome Biol Evol 2:212–224
Méndez C, Salas JA (1998) ABC transporters in antibiotic-producing actinomycetes. FEMS Microbiol Lett 158:1–8
Méndez C, Salas JA (2001) The role of ABC transporters in antibiotic-producing organisms: drug secretion and resistance mechanisms. Res Microbiol 152:341–350
Menges R, Muth G, Wohlleben W, Stegmann E (2007) The ABC transporter Tba of Amycolatopsis balhimycina is required for efficient export of the glycopeptide antibiotic balhimycin. Appl Microbiol Biotechnol 77:125–134
Olano C, Rodriguez AM, Mendez C, Salas JA (1995) A second ABC transporter is involved in oleandomycin resistance and its secretion by Streptomyces antibioticus. Mol Microbiol 16:333–343
Ostash B, Walker S (2010) Moenomycin family antibiotics: chemical synthesis, biosynthesis, biological activity. Nat Prod Rep 27:1594–1617
Ostash I, Ostash B, Walker S, Fedorenko V (2007) Proton-dependent transporter gene lndJ confers resistance to landomycin E in Streptomyces globisporus. Rus J Genet 43:852–857
Ostash I, Rebets Yu, Ostash B, Kobylyanskyy A, Walker S, Myronovskyy M, Nakamura T, Walker S, Fedorenko V (2008) An ABC transporter encoding gene lndW confers resistance to landomycin E. Arch Microbiol 190:105–109
Ostash B, Doud E, Ostash I, Lin C, Fuse S, Perlstein D, Walker S (2009) Complete characterization of the seventeen-step moenomycin biosynthetic pathway. Biochemistry 48:8830–8841
Ostash B, Doud E, Fedorenko V (2010a) The molecular biology of moenomycins: towards novel antibiotics based on inhibition of bacterial peptidoglycan glycosyltransferases. Biol Chem 391:499–504
Ostash B, Yan X, Fedorenko V, Bechthold A (2010b) Chemoenzymatic and bioenzymatic synthesis of carbohydrate containing natural products. Top Curr Chem 297:105–148
Ostash B, Rebets Yu, Myronovskyy M, Tsypik O, Ostash I, Kulachkovskyy O, Datsuk Y, Nakamura T, Walker S, Fedorenko V (2011) Identification and characterization of Streptomyces globisporus 1912 regulatory gene lndYR that affects sporulation and antibiotic production. Microbiology 157:1240–1249
Sambrook J, Russell DW (2001) Molecular cloning, a laboratory manual, 3rd edn. Cold Spring Harbor Laboratory Press, New-York
Sanchez C, Mendez C, Salas JA (2006) Indolocarbazole natural products: occurrence, biosynthesis, and biological activity. Nat Prod Rep 23:1007–1045
Sattler A, Kreuzig F (1975) The diumycin complex. Comparative studies on antibiotics from diumycin- and macarbomycin-fermentations. J Antibiot 28:200–204
Sheldon PJ, Mao Y, He M, Sherman DH (1999) Mitomycin resistance in Streptomyces lavendulae includes a novel drug-binding-protein-dependent export system. J Bacteriol 181:2507–2512
Sletta H, Borgos SE, Bruheim P et al (2005) Nystatin biosynthesis and transport: nysH and nysG genes encoding a putative ABC transporter system in Streptomyces noursei ATCC 11455 are required for efficient conversion of 10-deoxynystatin to nystatin. Antimicrob Agents Chemother 49:4576–4583
Song E, Malla S, Yang YH, Lee K, Kim EJ, Lee HC, Sohng JK, Oh MK, Kim BG (2011) Proteomic approach to enhance doxorubicin production in panK-integrated Streptomyces peucetius ATCC 27952. J Ind Microbiol Biotechnol 38:1245–1253
Yuan Y, Fuse S, Ostash B, Sliz P, Kahne D, Walker S (2008) Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design. ACS Chem Biol 3:429–436
Acknowledgments
The work was supported by grant Bg-98F from the Ministry of Education and Science of Ukraine and by NIH grant 2P01AI083214-04 (to S.W.). The usage of Agilent 6,520 Q-TOF spectrophotometer was supported by the Taplin Funds for Discovery Program (P.I.: S.W.).
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by Jean-Luc Pernodet.
Rights and permissions
About this article
Cite this article
Ostash, B., Doud, E. & Walker, S. ABC transporter genes from Streptomyces ghanaensis moenomycin biosynthetic gene cluster: roles in antibiotic production and export. Arch Microbiol 194, 915–922 (2012). https://doi.org/10.1007/s00203-012-0827-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00203-012-0827-9