s resistant to original compounds.tetracyclines, pyrolinomethyltetracycline, metamycin and doxycycline, exhibit a greater solubility and somewhat different antimicrobial spectrum, as compared to the original tetracyclines [15]. New derivatives of aminoglycosides have been obtained by chemical and enzymatic modifications.synthesis of antibiotics.As the majority of antibiotics have rather complex structures, their chemical synthesis is mostly more expensive than the production by fermentation. An exception to the rule seems to be chloramphenicol, that is normally prepared using a chemical synthesis.
Hybrid antibiotics. Using of genetic engineering we can combine structural genes of different antibiotic producers to obtaining new products which are not present in nature. If these genes are expressed, a hybrid antibiotic is synthesized, that can not be found in nature. Hopwood et al. [16] used this method with the genes of actinorhodin synthesis and obtained related hybrid macrolides, mederhodin A and B, dihydromederhodin A and dihydrogranatirhodin. Niemi et al. [16] prepared new anthracyclines by combination of DNA Streptomyces purpurascens.
. 2 Resistance to antibiotics
The antibiotic resistance is usually looked at from two angles: first, how the microbial strains arise, that obtain the resistance during the treatment of the macroorganism with the antibiotic, second, the resistance of microorganisms producing antibiotics that build up their resistance against the product of their own which, synthesized at high concentrations, would damage the producer. The ways of how these two types of resistance are achieved are often similar, even though the aims are different. Whereas a resistant microorganism is most often capable of transforming the antibiotic or even degrading it completely, the resistance of producing microorganisms has to ensure that the antibiotic will not be destroyed.
Resistance of antibiotic producers. The basic metabolic processes of microorganisms producing antibiotics are not inhibited, if the antibiotics are synthesized at low concentrations, observed in strains isolated from nature. By strain improvement, mutants have been able to reach 100 to 1000-fold antibiotic yields, as related to a volume unit of the fermentation medium. Genome changes of the improved strains include a number of deletions and amplifications in the chromosomal DNA. Changes in extrachromosomal DNA were also detected.
Low production strains, whose resistance to the own product is low (ie higher concentrations of the product inhibit their growth), regulate the antibiotic production, eg by inhibiting the enzyme activities that participate in the synthesis of the antibiotic. In high production strains, such a control is lost and the strains have to find a way how to survive in the presence of a high concentration of the antibiotic without decomposing it.As mentioned above, the genes for resistance to the own product are often located at the beginning of the cluster of structural genes. As a result, they are expressed simultaneously with the structural genes. However, the genes of newly gained resistances are mostly located on plasmids. Many antibiotics inhibit protein synthesis, the target site being at the ribosome level. Often, the functions of Tu and G elongation factors are also impaired, together with the synthesis of guanosin penta- and tetraphosphates that is significantly reduced. The antibiotic producers (mostly actinomycetes), as well as the bacteria against which the antibiotic is used, protect themselves by posttranscriptional modification of rRNA. Adenine is methylated to obtain N 6 -dimethyladenine rRNA in 23S. Such modified ribosomes do not bind the antibiotic. In other cases, adenine is methylated to yield 2-O-methyladenosine.
The most important mechanism of resistance observed in the antibiotic producers seems to be the transport of the antibiotic from the cell to the environment. In the case of high production rates, probably no protection of the active centres could be sufficiently effective. In addition, the antibiotic produced would gradually fill up the interior of the cell. In Streptomyces rimosus, an oxytetracycline producer, genes for the enzymes increasing the antibiotic transport rate precede the structural genes on the chromosome. Genes for the resistance consisting in the protection of ribosomes via the synthesis of an unidentified protein are located at the end of the structural gene cluster [17].
Antibiotic producers also have to solve the problem of a reverse flow of the antibiotic into the cell. Some antibiotics bind to the cell wall, others are complexed in the medium (tetracyclines in the presence of Ca 2+ ions). Cytoplasmic memb...
