Gene is the manipulator of life. It consists of a large number of nucleic acids and is responsible for the direction of metabolism throughout the life of a cell. They direct the synthesis of protein, control the production of enzymes, and are responsible for the transfer of genetic information from one offspring to another. Many antibacterial drugs can inhibit nucleic acid synthesis pathway to kill pathogenic bacteria. Creative Biolabs has developed an excellent drug discovery platform to determine the mode of action related with nucleic acid synthesis for antibacterial drugs.
The mechanisms of antibiotics that interfere with nucleic acid synthesis (nucleic acid inhibitor) can be divided into two main classes: (1) DNA inhibitor, mainly inhibition enzymes associated with DNA replication; (2) RNA inhibitor, inhibition of RNA transcription. By now, several antibiotics targeting on DNA and RNA synthesis have been identified.
Inhibition of DNA Replication
Examples of antibiotics that inhibit DNA replication include the quinolones and coumarin. The quinolones can selectively bind to the A subunit of DNA gyrase (aka topoisomerase II) at exposed single strand ends of the cut DNA chain. Hence, DNA gyrase becomes unable to reseal the newly-generated DNA and result in highly fragmented chromosome. Topoisomerase inhibition caused by quinolones leads to many double-stranded DNA breaks, which can induce the DNA stress response (SOS response). During this process, RecA is activated by DNA damage and promotes auto-cleavage of the LexA repressor protein. The auto-cleavage subsequently induces expression of SOS-response genes including DNA repair enzymes.
Coumarin, including coumermycin and novobiocin, are natural antibiotics produced by Streptomyces. Coumarin inhibits type II topoisomerases, DNA gyrase and topoisomerase IV. But the mechanism of coumarin is different from that of quinolones. They act by competitive inhibition of ATP hydrolysis by the B subunit of DNA gyrase and the subunit ParE for topoisomerase IV.
Figure 1. Inhibition of quinolones in DNA replication (Kohanski et al. 2010)
Inhibition of RNA Transcription
The MOA of rifamycin class of semi-synthetic bactericidal antibiotics is inhibition of RNA transcription which has a catastrophic effect on the prokaryotic organism. Rifamycin drugs inhibit DNA-dependent transcription by stable binding, with high affinity, to the subunit of a DNA-bound and actively transcribing RNA polymerase enzyme. A unique mechanistic requirement of rifamycins is that RNA synthesis has not progressed beyond the addition of two ribonucleotides. It can promote the drug molecules to sterically inhibit nascent RNA strand initialization.
Creative Biolabs' professional group has the ability to determine the mode of action for new antibacterial drugs. For more detailed information, please feel free to contact us or directly sent us an inquiry.
Reference
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