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Nalidixic acid and other first generation quinolones (i.e., oxolinic acid) are rarely used today owing to their toxicity 17. Quinolones are derivatives of nalidixic acid, which was discovered as a byproduct of chloroquine (quinine) synthesis and introduced in the 1960s to treat urinary tract infections 16. These reactions are exploited by the synthetic quinolone class of antimicrobials, including the clinically-relevant fluoroquinolones, which target DNA-topoisomerase complexes 4, 14, 15. Modulation of chromosomal supercoiling through topoisomerase-catalyzed strand breakage and rejoining reactions is required for DNA synthesis, mRNA transcription and cell division 11 – 13. Inhibition of DNA replication by quinolones We also describe recent efforts in network biology that have yielded novel, mechanistic insights into how bacteria respond to lethal antibiotic treatments, and discuss how these insights and related developments in synthetic biology may be used to develop new, effective means to combat bacterial infections.
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Here we review our current knowledge of the drug-target interactions and associated mechanisms by which the major classes of bactericidal antibiotics kill bacteria. More specifically, treatment with lethal concentrations of bactericidal antibiotics results in the production of harmful hydroxyl radicals through a common oxidative damage cellular death pathway involving alterations in central metabolism (TCA cycle) and iron metabolism 8 – 10. Additionally, recent evidence points toward a common mechanism of cell death, involving disadvantageous cellular responses to drug-induced stresses that are shared by all classes of bactericidal antibiotics, which ultimately contributes to killing by these drugs 8.
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The increasing prevalence of drug-resistant bacteria 3, as well as the means of gaining resistance, has made it crucial that we better understand the multilayered mechanisms by which currently available antibiotics kill bacteria, as well as explore and find alternative antibacterial therapies.Īntibiotic-induced cell death has been associated with the formation of double-stranded DNA breaks following treatment with DNA gyrase inhibitors 4, with the arrest of DNA-dependent RNA synthesis following treatment with rifamycins 5, with cell envelope damage and loss of structural integrity following treatment with cell-wall synthesis inhibitors 6, and with cellular energetics, ribosome binding and protein mistranslation following treatment with protein synthesis inhibitors 7. Antibiotic-mediated cell death, however, is a complex process that begins with the physical interaction between a drug molecule and its bacterial-specific target, and involves alterations to the affected bacterium at the biochemical, molecular and ultrastructural levels. These efforts have significantly enhanced our clinical armamentarium. Since the discovery of penicillin was reported in 1929 2, other, more effective antimicrobials have been discovered and developed by elucidation of drug-target interactions, and by drug molecule modification.
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Most current bactericidal antimicrobials, which are the focus of this review, inhibit DNA synthesis, RNA synthesis, cell wall synthesis, or protein synthesis 1. Antibiotics can be classified based on the cellular component or system they affect, in addition to whether they induce cell death (bactericidal drugs) or merely inhibit cell growth (bacteriostatic drugs). Our understanding of how antibiotics induce bacterial cell death is centered on the essential cellular function inhibited by the primary drug-target interaction.