Mechanism of action of ciprofloxacin DNA synthesis is interfered by sealing DNA gyrase

Mechanism of action of ciprofloxacin
DNA synthesis is interfered by sealing DNA gyrase ( topoisomerase II ) and topoisomerase IV. Two sets of subunits, 2GyrA and 2GyrB that are encrypted by genes gyrA and gyrB severally consists DNA gyrase enzyme. DNA rupturing and association are processed by genes gyrA. Unique negative supercoiling continuation of DNA gyrase is processed by C-terminus of GyrA subunit and any mutation that cause absence of C-terminus of GyrA subunit unable to form negative supercoils. Targeting DNA gyrase is so effective as it is absent in eukaryotic cells and is fundamental for bacterial proliferation. In addition to, two sets of subunits, 2ParC and 2parE that are enciphered by genes parC and parE respectively comprise topoisomerase IV. It denotes two vital roles. Firstly it acts as decatenating enzyme and terminates interconnected daughter chromosomes to separate chromosomes into daughter cells after DNA replication. Thus cell division can be done. Secondly, topoisomerase IV loosens up positive supercoil with the help of DNA gyrase. The important physiologic fuction of both DNA gyrase ( topoisomerase II ) and topoisomerase IV, is the replication and transcription of DNA and decantation of daughter cells by topoisomerase IV following DNA replication. It is evident that topoisomerase II acts before the replication fork while topoisomerase IV functions after the replication fork on freshly made DNA. Ciprofoxacin interferes functions of both of the enzymes in bacteria.

Mechanisms of resistance
Target enzyme resistance mechanism: Amino acid substitutions occur in a region of the GyrA or ParC subunit. These mutations in gyrase and topoisomerase-DNA IV are called “quinolone-resistance-determining region“ (QRDR). This region exists on the DNA-binding surface of the enzyme. These substitutions reduce vulnerability by declining drug affinity and also weaken or damage target enzyme function.

2) Plasmid-mediated resistance:
a) Qnr gene generates a 219 amino acid protein that reduce topoisomerase-DNA binding and defend enzyme-DNA complexes from ciprofloxacin. b) Another resistance mechanism is that aac (6`)-lb cr aminoglycoside acetyltransferase acetylates free nitrogen on C7 ring of ciprofloxacin. Thus, potency of drug is decreased.

c) The concentrations of ciprofloxacin in the cell are reduced by plasmid encoded efflux pumps. Thus resistance to ciprofloxacin has been obtained.

Chromosome mediated resistance:
a) If porins in gram-negative species are abnormally underexpressed, drug uptake is decreased.
b) If chromosome encoded efflux pumps are overexpressed, drug retention in the bacterial cells are decreased. Thus, resistance to ciprofloxacin can grow.

Reference:  Fàbrega, A., Madurga, S., Giralt, E. and Vila, J. (2009). Mechanism of action of and resistance to quinolones. Microbial Biotechnology, online 2(1), pp.40-61. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815421/pdf/mbt0002-0040.pdf Accessed 29 Oct. 2018.

 Aldred, K., Kerns, R. and Osheroff, N. (2014). Mechanism of Quinolone Action and Resistance. Biochemistry, online 53(10), pp.1565-1574. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985860/pdf/bi5000564.pdf Accessed 29 Oct. 2018.