Gabriel Raffai

BCH 561

Mechanism of Action of Antibiotics that Inhibit DNA Function, Replication and Transcription

 

This category of antibiotics that interfere with nucleic acid polymerization can be divided into two main classes: (1) those that perturb the template function of DNA; (2) those that inhibit the enzymes associated with DNA replication and transcription. The former class can be divided into those that chemically modify DNA and those that form complexes with DNA. One example of those that chemically modify DNA is the mitomycins. They bind covalently and irreversibly to DNA and show very little selectivity. Thus, they are very toxic and are not used as antibiotics. The bleomycins are a group of less toxic antibiotics that act by producing multiple breaks in both single and double-stranded DNA. However, they are used only against certain types of tumors. Two final examples of antibiotics that chemically modify DNA are the imidazole derivatives (i.e. metronidazole) and the nitrofurans (i.e. nitrofurantoin). Metronidazole is 90-100% effective against sexually transmitted urogenital infections caused by Trichomonas vaginalis. Nitrofurantoin is used in the treatment of urinary tract infections. Both antibiotics act by inducing breakage in DNA strands via direct chemical interaction. Specifically, the nitro group of the antibiotic is converted to a nitronate radical in the cell. The radical form of the antibiotic is the activated form that actually attacks and breaks DNA strands. One example of the antibiotics that form complexes with DNA—also known as intercalators—is actinomycin D. However, like the mitomycins, they are highly toxic and of limited use. Two other examples are daunorubicin and doxorubicin that are among the most effective anti-tumor antibiotics. They indirectly cause via intercalation multiple breaks in the DNA strand.

As mentioned above, there are also antibiotics that act by inhibiting enzymes associated with DNA replication and transcription. Examples of those that inhibit DNA replication include the quinolones, coumermycins and novobiocin. The quinolones selectively inhibit DNA gyrase (aka topoisomerase II) by binding to the A subunit of the enzyme at exposed single strand ends of the cut DNA chain. Hence, DNA gyrase becomes unable to reseal the DNA with the end result that the chromosome becomes highly fragmented. Quinolones include nalidixic acid and oxolinic acid, but the newer second-generation quinonlones—the 4-fluoroquinolones (i.e. norfloxacin and ciprofloxacin)—are much more effective. The coumermycins and novobiocin also inhibit DNA gyrase but by binding to the ATP site on the B subunit. It is useful to note that there is no cross resistance between these two types of antibiotics that affect DNA replication. In addition, to date, no specific inhibitor of bacterial DNA polymerases has been reported.

Examples of those antibiotics that inhibit DNA transcription include the rifamycins (included in the ansamycins), streptolidigin and lipiarmycin. Some common characteristics of these antibiotics is that they are very selective against RNA polymerase, they do not directly affect DNA synthesis and they are bacteriostatic unless the complex formed with the enzyme is virtually irreversible. Lipiarmycin is a true inhibitor of RNA synthesis initiation whereas the exact mechanism of action of the rifamycins is debatable. According to one source1 they act by inhibiting the initiation stage of transcription in which the first nucleotide is incorporated into the mRNA. According to another2 they act by inhibiting formation of the second phosphodiester bond of mRNA and thus the elongation of it. What is known with certainty is that the rifamycins form a virtually irreversible complex with the beta subunit of RNA polymerase. They are highly effective agents in treating tuberculous meningitis and staphylococci infections.

 

 

 

References

 

  1. Hugo, W. B., and Russell, A. D. 1998. Pharmaceutical Microbiology, 6th edition, Blackwell Sciences Ltd., Oxford.
  2. Lancini, G., Parenti, F., and Gallo, G. G. 1995. Antibiotics: A Multidisciplinary Approach, Plenum Press, New York.