Bicyclomycin
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| Trade names | bicozamycin |
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| Formula | C12H18N2O7 |
| Molar mass | 302.3 g/mol |
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Bicyclomycin (Bicozamycin) is a broad spectrum antibiotic active against Gram-negative bacteria and the Gram-positive bacterium, Micrococcus luteusn that was isolated from Streptomyces sapporonesis and Streptomyces aizumenses in 1972. It belongs to a class of naturally occurring 2,5-diketopiperazines, that are among the most numerous of all the naturally occurring peptide antibiotics. This clinically useful antibiotic is rapidly absorbed in man when given intramuscularly, has low toxicity and has been used to treat diarrhea in humans and bacterial diarrhea in calves and pigs.
Bicyclomycin is the only known selective inhibitor of Rho, a RecA-type ATPase, which is a transcription termination factor in Escherichia coli. X-ray crystallographic images of the bicyclomycin-rho complex have been used to define the rho antibiotic-binding site and understand the molecular basis for its mode of action.
Bicyclomycin is a crystalline, colorless, water-soluble, and weakly basic substance (mp 187-189 oC) that is soluble in methanol, and sparingly in ethanol, is practically insoluble in most organic solvents, and is unstable in alkaline solution.
In an attempt to increase the potency and its antimicrobial spectrum, a series of synthetic and semisynthetic derivatives were investigated. Structure–activity relationship (SAR) studies have shown that the C(1) triol and the [4.2.2]-bicyclic ring were essential for bicyclomycin-rho inhibitory activity whereas the C(5)−C(5a) exomethylene moiety was not. Further SAR studies showed that 5a-substituted derivatives can be prepared that were an order of magnitude more efficient than bicyclomycin in the inhibition of rho. Bicyclomycin is considered a weak antibiotic and when used alone, bicyclomycin failed to rapidly kill growing cultures of Escherichia coli; however, the additional presence of bacteriostatic concentrations of inhibitors of gene expression such as tetracycline, chloramphenicol or rifampicin led to rapid killing. This lethal synergy has been considered as one way to address the growing problem of antimicrobial resistance.
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