Fluoroquinolones: Mechanisms of Action and Resistance

in this animation we demonstrate the biology of DNA replication leading to bacterial cell division in a gram positive bacteria such as s pneumonia the DNA is shown as a circular double strand in the bacterial cell like the DNA of all living organisms it contains the unique genetic code for all of the proteins required for bacterial survival bacteria replicate by a process known as binary fission whereby one bacterium separates into two new daughter cells however before this can occur the bacterium must make an identical copy of its complete circular DNA DNA replication requires that the two strands of DNA separate so that the genetic code of the bacterium can be read and a new complementary strand can be created for each of the original strands to accomplish this various enzymes known as helicases break the hydrogen bonds between the bases in the two DNA strands unwind the strands from each other and stabilize the exposed single strands preventing them from joining back together the points at which the two strands of DNA separate to allow replication of DNA are known as replication forks the enzymes is DNA polymerase then moves along each strand of DNA behind each replication fork synthesizing new DNA strands in red complementary to the original ones as a replication forks move forward positive super helical twists in the DNA begin to accumulate ahead of them in order for DNA replication to continue these super helical twists must be removed the bacterial enzyme DNA gyrase which is also known as topoisomerase 2 is responsible for removing the positive super helical twists so that DNA replications can precede DNA gyrase is an essential bacterial enzyme composed of 2a and 2b subunits which are products of the gy ra and gy RB genes this enzyme has other important functions which affect the initiation of DNA replication and transcription of many genes with the combined involvement of these enzymes an entire duplicate copy of the bacterial genome is produced as the two replication forks move in opposite directions around the circular DNA genome eventually as the two replication forks meet two new complete chromosomes have been made each consisting of one old and one new strand of DNA this is referred to as semiconservative replication in order to allow the two new interlinked chromosomes to come apart another bacterial enzyme is needed which is known as topoisomerase for this enzyme is structurally related to DNA gyrase and is coded for by the Parc and PA our genes topoisomerase 4 allows for the two new interlinked chromosomes to separate so that they can be segregated into two new daughter bacterial cells this animation will demonstrate two mechanisms of fluoroquinolone action fluoroquinolone antibiotics shown here are synthetic molecules that are bacterial seidel the potency of these drugs is greatly improved by the addition of a fluorine molecule at position 6 and thus the term fluoroquinolones fluoroquinolones rapidly inhibit bacterial DNA synthesis resulting in bacterial cell death although much is known about the molecular events that underlie the action of quinolone antibiotics much remains to be clarified fluoroquinolones act by inhibiting the activity of both the DNA gyrase and the topoisomerase for enzymes for most gram-negative bacteria DNA gyrase is the primary fluoroquinolone target fluoroquinolones have been shown to bind specifically to the complex of DNA gyrase and DNA rather than the DNA gyrase alone as a result of this binding quinolones appeared to stabilize the enzyme DNA complexes which in turn results in breaks in the DNA that are fatal to the bacterium a second mechanism of fluoroquinolone action is shown here with some exceptions topoisomerase 4 is the primary target of fluoroquinolone action in most gram positive bacteria such as staphylococci and streptococci with DNA gyrase being a secondary target the separation of two new internet daughter strands of circular DNA is disrupted the final result on the bacteria however is the same bacterial replication is disrupted and the bacterium breaks apart the relative potency of different fluoroquinolone antibiotics and thus their spectrum of activity is dependent in part on their affinity for either DNA gyrase or topoisomerase for or both one of the most common mechanisms by which bacteria acquire resistance to fluoroquinolones is by spontaneously occurring mutations in chromosomal genes that alter the target enzymes DNA gyrase and topoisomerase for or both the frequency with which these spontaneous mutations occurs may be in the range of 10 to the power of negative 6 the effective mutations on the activity of an individual fluoroquinolone will vary depending on the number of mutations the location of the mutations and which target enzyme is affected if a mutation occurs either in the Gyr a or gy RB gene that alters DNA gyrase and results in a reduced affinity of the fluoroquinolone antibiotic for this enzyme the organism will become resistant similarly a mutation may occur that alters topoisomerase for either in the parc or PA are a gene and results in a reduced affinity of the fluoroquinolone antibiotic for this enzyme and the bacterial organism will become resistant it is important to note that for some fluoroquinolones that have similar affinity and potency against both target enzymes mutations in both DNA gyrase and topoisomerase 4 will be needed for resistance to occur in resistant organisms semiconservative replication continues

Channel: Mechanisms in Medicine

Views: 503,283

Keywords: Antibiotic resistance, antibiotic, antimicrobial resistance, Bacteria, DNA, chromosome, DNA gyrase, DNA polymerase, DNA replication, fluoroquinolone, gatifloxacin, gram negative bacteria, gram positive bacteria, helicase, levofloxacin, Mechanism of drug resistance, moxifloxacin, ofloxacin, stereochemistry, quinolone, pneumonia, Staphylococci, Streptococci, Supercoiling, superhelical, Topoisomerase, Mechanisms in Medicine, Mechanisms, E.coli

Id: IkKZ_gxAOXI

Length: 7min 7sec (427 seconds)

Published: Tue Mar 29 2011