Source+5


 * Cirz RT, Chin JK, Andes DR, de Crécy-Lagard V, Craig WA, et al. //Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance//. PloS Magazine. June 2005.

[](what happens to overused antibiotics, evolution)


 * "Today, resistance has rendered most of the original antibiotics obsolete for many infections, mandating an increased reliance on synthetic drugs." (paragraph 1)
 * "However, bacteria also evolve resistance to these drugs, typically by acquiring chromosomal mutations [[|1�6]]." (paragraph 1)
 * "However, recent evidence suggests that bacteria may play a more active role in the mutation of their own genomes in response to at least some DNA-damaging agents by inducing proteins that actually promote mutation [[|7–15]]." (paragraph 1)
 * "Ciprofloxacin is a member of the quinolone family of antibiotics, which is rapidly becoming the most important family of antibiotics [[|16]]." (paragraph 2)
 * "Quinolones function by interfering with the two essential type II DNA topoisomerases in bacteria, gyrase and topoisomerase IV [[|17]]." (paragraph 2)
 * "These topoisomerases normally function by forming a protein-bridged DNA double strand break (DSB), manipulating DNA strand topology, and finally rejoining the DNA ends." (paragraph 2)
 * "Ciprofloxacin reversibly binds to the protein-bridged DSB intermediate and inhibits rejoining of the DNA ends." (paragraph 2)
 * "The toxic effects of ciprofloxacin may be the result of topoisomerase subunit dissociation without re-ligation of the DNA ends [[|17],[|18]], likely producing free double strand ends (DSEs) when the protein-DNA bond is eventually hydrolyzed or the DNA is processed by a nuclease." (paragraph 2)
 * In addition, covalently bound topoisomerases may also block DNA replication forks, which after processing will also produce DSEs [[|17],[|19–23]]." (paragraph 2)
 * "Resistance to ciprofloxacin requires mutations in the genes that encode the topoisomerases (//gyrA// and //gyrB//, encoding gyrase, and //parC// and //parE//, encoding topoisomerase IV) or in the genes that affect cell permeability or drug export [[|1],[|17]]." (paragrph 2)
 * "Because ciprofloxacin may induce repair pathways that involve RecA-ssDNA filament formation, the drug itself may act to induce the mutations that confer resistance." (paragraph 4)
 * "This hypothesis is consistent with observations that quinolones can be mutagenic and can induce the SOS response" (paragraph 4)
 * "Here, using an in vivo infection model, we show that interfering with LexA autoproteolysis renders pathogenic Escherichia coli unable to mutate and acquire resistance to ciprofloxacin. The same result is demonstrated in vivo for the antibiotic rifampicin, which is a semisynthetic member of the rifamycin class of antibiotics that inhibits the bacterial RNA polymerase." (paragraph 4)
 * "If the acquisition of antibiotic resistance-conferring mutations also requires the induction of these proteins, then their inhibition would represent a novel approach to combating the growing problem of drug resistance." (paragraph 1)
 * "These topoisomerases normally function by forming a protein-bridged DNA double strand break (DSB), manipulating DNA strand topology, and finally rejoining the DNA ends." (paragraph 2)