Streptomyces clavuligerus was originally isolated from a South American soil sample for its ability to produce cephalosporins and penicillin N. It also produces cephamycins, such as deacetoxycephamycin C, and the commercially-relevant clavulanic acid. The name "clavuligerus" comes from the latin word clavula, which stands for "little club" and the suffix -igerus, which stands for "bearing". This refers to the morphology of the hyphae and the spores under a microscope. When S. clavuligerus sporulates, it produces a greyish-greenish pigment depending on the type of media it grows on(1).
S. clavuligerus is the industrial producer of the beta-lactamase inhibitor, clavulanic acid, that reduces the MIC of antibiotics used against b-lactamase producing strains of Staphylococcus, Klebsiella, Pseudomonas and E. coli. Due to its beta-lactamase inhibiting properties, clavulanic acid is co-formulated with amoxicillin, for which the generic name is co-amoxiclav. The biosynthetic pathway in S. clavuligerus has been almost completely deciphered (Jensen and Paradkar, 1999). Approaches to increase the yield of clavulanic acid as a fermentation product encompass fermentation optimisation approaches, as well as genetic modification for metabolic tailoring/engineering. S. clavuligerus differs from most other Streptomyces in that the wildtype is unable to take up sufficient amounts of glucose for it to utilise it as a sole carbon source (4). This has been attributed to the low expression levels of the glucose uptake protein, glucose permease, encoded by glcP (5). This is despite the glcP gene and the glucokinase gene, (glk), being present on the genome. The combination of the glucose permease and glucokinase has been shown to function as the main glucose uptake system in the model organism S. coelicolor(6,7).
Unlike most Streptomyces, S. clavuligerus does not sporulate on MS medium but can be grown on GYM medium for sporulation. Aside from GYM, wildtype grows well on TSB agar and DNA.
For cultivation in liquid, TSB medium gives the best result for dispersed growth. For growth curves in liquid, it is best to heat-active spores for 10 minutes at 50° prior to pre-germing for 12 - 24 hours (usually 10 ml of medim). Absorbance measurement readings at 600 nm wavelength can be used up until roughly 48 hours into the growth curve, cell dry weight, however, will give a more accurate result.
The genome of S. clavuligerus type strain ATCC 2764 has been analysed on several occasions, either by whole genome sequencing (8,9) or PFGE (10). It consists of a chromosome of 6.8 Mb that encodes 25 putative secondary metabolite clusters, including the clavulanic acid and cephamycin C clusters (11), and 4 linear plasmids: pSCL1 (11 kb), pSCL2 (150 kb), pSCL3 (455 kb) and pSCL4 (1,800 b). pSCL4 is a giant linear plasmid and it is the largest linear plasmid published to date and carries 17 putative secondary metabolite clusters including antibiotics such as staurosporine, moenomycin and other β-lactams.
Browse the S. clavuligerus genome and antiSMASH output via the ActinoBase MORF Genome Browser.
|Replicon||Size (kb)||GC %||Coding sequences||2ary metabolite clusters||Examples of 2ary metabolites|
|Chromosome||6,760||72.7||5,900||25||clavulanic acid, cephamycin C, holomycin|
- Higgens, C. E. and Kastner, R. E. (1971) ‘Streptomyces clavuligerus sp. nov., a β-lactam antibiotic producer’, International Journal of Systematic and Evolutionary Microbiology. Microbiology Society, 21(4), pp. 326–331.
- Howarth, T. T., Brown, A. G. and King, T. J. (1976) ‘Clavulanic acid, a novel β-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis’, Journal of the Chemical Society, Chemical Communications. Royal Society of Chemistry, (7), p. 266b–267.
- Jensen, S. E. and Paradkar, A. S. (1999) ‘Biosynthesis and molecular genetics of clavulanic acid’, Antonie Van Leeuwenhoek. Springer, 75(1), pp. 125–133.
- Garcia-Dominguez, M., Martin, J. F. and Liras, P. (1989) ‘Characterization of sugar uptake in wild-type Streptomyces clavuligerus, which is impaired in glucose uptake, and in a glucose-utilizing mutant.’, Journal of bacteriology. Am Soc Microbiol, 171(12), pp. 6808–6814.
- Pérez-Redondo, R., Santamarta, I., Bovenberg, R., Martín, J. F. and Liras, P. (2010) ‘The enigmatic lack of glucose utilization in Streptomyces clavuligerus is due to inefficient expression of the glucose permease gene’, Microbiology. Microbiology Society, 156(5), pp. 1527–1537.
- Van Wezel, G. P., Mahr, K., König, M., Traag, B. A., Pimentel‐Schmitt, E. F., Willimek, A. and Titgemeyer, F. (2005) ‘GlcP constitutes the major glucose uptake system of Streptomyces coelicolor A3 (2)’, Molecular microbiology. Wiley Online Library, 55(2), pp. 624–636.
- Van Wezel, G. P., König, M., Mahr, K., Nothaft, H., Thomae, A. W., Bibb, M. and Titgemeyer, F. (2007) ‘A new piece of an old jigsaw: glucose kinase is activated posttranslationally in a glucose transport-dependent manner in Streptomyces coelicolor A3 (2)’, Journal of molecular microbiology and biotechnology. Karger Publishers, 12(1–2), pp. 67–74.
- Medema, M.H. et al., 2010. The sequence of a 1.8-Mb bacterial linear plasmid reveals a rich evolutionary reservoir of secondary metabolic pathways. Genome Biology and Evolution, 2(1), pp.212–224.
- Song, J.Y. et al., 2010. Draft genome sequence of Streptomyces clavuligerus NRRL 3585, a producer of diverse secondary metabolites. Journal of Bacteriology, 192(23), pp.6317–6318.
- Netolitzky, D.J. et al., 1995. Giant linear plasmids of beta-lactam antibiotic producing Streptomyces. FEMS Microbiology Letters, 131(1), pp.27–34.
- Chen, C.W. et al., 1994. The linear chromosomes of Streptomyces: structure and dynamics. Actinomycetologica, 8, pp.103–112.