Bacterial Pharmaceutical Products
Bacterial pharmaceutical products include antibiotics, antitumor agents, immunomodulators, and enzyme inhibitors. Other bioactive products of bacterial origin are coccidiostatic agents, nematicides, and insecticides. In addition, Escherichia coli, the prototype of molecular biology, is one of the most important hosts for the production of pharmaceutical recombinant proteins.
The approach to antibiotic discovery, denoted as “screening,” proposed by Waksman in 1940, was so effective that by the end of the 1950s, members of all the main families of clinically useful antibiotics were discovered. In the following years, the screening concepts were refined, introducing methods to select organisms which were potential producers of novel antibiotics and orienting the screening toward biochemical targets rather than general activities. The approach was successful, and many interesting products were identified in the period of 1960–1980. In the following decades, the research was mainly driven by the need to stop the spread of antibiotic multiresistant strains due to the horizontal transmission of resistance genes. Some important success has been obtained, mainly by target-oriented modification of members of classical families of antibiotics.
Most of the clinically effective antitumor agents were discovered in the 1960s by testing against tumor cell lines the active metabolites which were too toxic for use as anti-infective drugs. Only recently, a new family of products, active by stabilizing microtubulins, has been discovered by a target-oriented screening.
Among the other bioactive metabolites, two products of Streptomyces have important clinical use as immunomodulators, and members of the avermectin family are largely used against nematode and arthropod infections. A family of exceptionally effective insecticides, the spinosins, receives an increasing share of the agricultural market.
Most of the bacteria producing therapeutically effective antibiotics are actinomycetes, organisms belonging to the order Actinomycetales. Most of the products are produced by member of the genus Streptomyces. The genetics and biochemistry of antibiotic production has been mainly studied in strains of this genus. Antibiotics are products of the secondary metabolism, a form of cellular chemical differentiation linked in time, and sharing some initiator genes with cell morphological differentiation. The biosynthetic pathways yielding the backbone of most molecules of actinomycete pharmaceutical products consist of five different polymerization mechanisms: (1) and (2) the iterative polyketide synthases and modular polyketide synthases formed from small carboxylic acids units, polyaromatic compounds, and aliphatic chains; (3) the thiotemplate mechanism of polypeptide synthesis, by which most of the peptide antibiotics are produced; (4) the ribosome-dependent amino acid polymerization, which synthesizes the peptide lantibiotics; and (5) the condensation of carbohydrate units forming the aminosaccharide antibiotics.
The genes governing the production of secondary metabolites are grouped in clusters, composed of structural genes encoding the enzymes catalyzing the synthesis of the molecule, and regulatory genes, determining the activation of the structural genes. During the growth phase of the Streptomyces life cycle, all the genes of the cluster are repressed. When the deprivation of an essential nutrient induces the onset of cell differentiation, a cascade of events activates the transcription of the regulatory genes, which in turn activate the genes governing the biosynthesis. Genetic studies have been essential in understanding the mechanisms of antibiotic synthesis regulation. Most relevant successes have been recently obtained by genetic engineering for the improvement of metabolite production, especially in orienting the production toward the preferred members of the metabolite complexes.
KeywordsSecondary Metabolism Clavulanic Acid Antibiotic Production Acyl Carrier Protein Secondary Metabolite Production
- Barriere JC, Berthaud N, Beyer D, Dutka-Malen S, Paris JM, Desnottes JF (1998) Recent developments in streptogramin research. Curr Pharm Design 4:155–180Google Scholar
- Chary VK, de la Fuente JL, Leitao AL, Liras P, Martin JF (2000) Overexpression of the lat gene in Nocardia lactamdurans from strong heterologous promoters results in very high levels of lysine6-aminotransferase and up to two-fold increase of cephamycin C production. Appl Microbiol Biotechnol 53:282–288PubMedCrossRefGoogle Scholar
- Debono M, Abbott BJ, Molloy RM, Fukuda DS, Hunt AH, Daupert VM, Counter FT, Ott JL, Carrell CB, Howard LC, Boeck LD, Hamill RL (1988) Enzymatic and chemical modifications of lipopeptide antibiotic L21978; the synthesis and evaluation of daptomycin (LY1146032). J Antibiot 41:1093–1105PubMedCrossRefGoogle Scholar
- Demain AL (1989) Function of secondary metabolites. In: Hershberger CL, Queener SW, Hegeman G (eds) Genetics and molecular biology of industrial microorganisms. ASM Press, Washington, DC, pp 1–11Google Scholar
- Ensign JC (1992) Introduction to actinomycetes. In: Balows A, Truper HG, Dworkin M, Harder W, Schleifer KE (eds) The prokaryotes, vol 1, 2nd edn. Springer, Berlin, pp 811–815Google Scholar
- Fleming ID, Nisbet LJ, Brewer SJ (1982) Target directed antimicrobial screens. In: Bulock JD, Nisbet LJ, Winstanley DJ (eds) Bioactive microbial products: search and discovery. Academic, London, pp 107–130Google Scholar
- Haney ME Jr, Hoehn MM (1968) Monensin, a new biologically active compound. 1: discovery and isolation. Antimicrob Agents Chemother 7:349–352Google Scholar
- Higgins DL, Chang R, Debobov DV, Leung J, Wu T, Krause KM, Sandvik E, Hubbard JM et al (2005) Telavancin, a multifunctional glycopeptides, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus. Antimicrob Ag Chemother 49:1127–1134CrossRefGoogle Scholar
- Hutchinson CR (1997) Antibiotics from genetically engineered microorganisms. In: Strohl W (ed) Biotechnology of antibiotics, 2nd edn. Marcel Dekker, New York, pp 683–702Google Scholar
- Lancini GC (2006) Forty years of antibiotic research at Lepetit: a personal journey. SIM News 56:192–212Google Scholar
- Lancini GC, Demain AL (1999) Secondary metabolism in bacteria: antibiotic pathways, regulation, and function. In: Lengeler JW, Drews G, Schlegel HG (eds) Biology of the prokaryotes. Thieme Verlag, Stuttgart, pp 627–651Google Scholar
- Lancini GC, Lorenzetti R (1993) Biotechnology of antibiotics and other bioactive microbial metabolites. Plenum Press, New York, pp 95–132Google Scholar
- Lancini GC, Parenti F, Gallo GG (1995) Antibiotics: a multidisciplinary approach. Plenum Press, New YorkGoogle Scholar
- Lazzarini A, Cavaletti L, Toppo G, Marinelli F (2001) Potentialities of rare actinomycetes as producers of new antibiotics. Ant v Leeuwenhoek 79:399–405Google Scholar
- Madduri K, Kennedy J, Rivola G, Inventi-Solari A, Filippini S, Zanuso G, Colombo AL, Gewain KM, Occi JL, MacNeil DJ, Hutchinson CR (1998) Production of the antitumor drug epirubicin (4′ epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius. Nat Biotechnol 16:69–74PubMedCrossRefGoogle Scholar
- McAlpine J (1998) Unnatural natural products by genetic manipulation. In: Sapienza DM, Savage LM (eds) Natural products II: new technologies to increase efficiency and speed. International Business Community, Southborough, MA, pp 251–278Google Scholar
- McArthur HIA (1998) The novel avermectin, doramectin – a successful application of mutasynthesis. In: Hutchinson CR, McAlpine J (eds) Proceedings, biotechnology of microbial products conference, (BMP 97), Society for Industrial Microbiology, Fairfax, VA, pp 43–48Google Scholar
- Moore M (1992) Strategic alliances: technological value in pharmaceutical drug discovery. Biofut Eur 9:138–143Google Scholar
- Parekh R (1989) Polypeptide glycosylation and biotechnology. Biotech Eur 6:18–21Google Scholar
- Rawls RL (1998) Polyketides: research increases on modular synthesis of these biomolecules by enzymes. Chem Eng News 76:29–30Google Scholar
- Stapley EO (1982) Avermectins, antiparasitic lactones produced by Streptomyces avermitilis isolated from a soil in Japan. In: Umezawa H, Demain AL, Hata R, Hutchinson CR (eds) Trends in antibiotic research. Antibiotic Research Association, Tokyo, pp 154–170Google Scholar
- Strohl WR (1997) Biotechnology of antibiotics, 2nd edn. Marcel Dekker, New YorkGoogle Scholar
- Strohl WR, Woodruff RL, Monaghan D, Hendlin H, Mochales S, Demain AL, Liesch L (2001) The history of natural products research at Merck and Co., Inc. SIM News 51:5–19Google Scholar
- Stutzman-Engwall H, Colon S, Fedechko R, McArthur H, Pekrun K, Chen Y, Jenne S, La C, Thrin N, Kim S, Zang XY, Fox R, Gustafsson C, Krebber A (2005) Semi-synthetic DNA shuffling of aveC leads to improved industrial scale production of doramectin by Streptomyces avermitilis. Metab Eng 7:27–37PubMedCrossRefGoogle Scholar
- Swartz JR (1996) Escherichia coli recombinant DNA technology. In: Neidhardt FC (ed) Escherichia coli and Salmonella: cellular and molecular biology, 2nd edn. American Society of Microbiology Press, Washington, DC, pp 1693–1711Google Scholar
- Tomasz M (1995) Mitomycin C: small, fast and deadly (but very selective). Curr Biol 2:575–579Google Scholar
- Umezawa H (1972) Enzyme inhibitors of microbial origin. University Park Press, BaltimoreGoogle Scholar
- Weinstein MJ (2004) Micromonospora antibiotic discovery at schering/schering-plough (1961–1973). SIM News 54:56–66Google Scholar
- Wesseling AC, Lago B (1981) Strain improvement by genetic recombination of cephamycin producers, Nocardia lactamdurans and Streptomyces griseus. Dev Ind Microbiol 22:641–651Google Scholar
- Woodruff HB, McDaniel LE (1958) Antibiotic approach in strategy of chemotherapy. Soc Gen Microbiol Symp 8:29–48Google Scholar