Antibiotics

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In current antimicrobial therapies two categories are distinguished. Bactericidal drugs that kill bacteria with an efficiency of over $99,9 \%$ and bacteriostatic drugs that just inhibit growth.

The well studied antibacterial drug interactions mainly fall into three classes:

  • Inhibition of DNA replication and repair (e.g. quinolones bind DNA gyrase (Topoisomerase III) complexed with DNA, leading to DNA break formation
    Fluorchinolones: e.g. Norfloxacin, Ciprofloxacin, Levofloxacin, Moxifloxacin
  • Inhibition of protein synthesis (glycosides target 30S and 50S ribosome subunits)
    Macrolides: e.g. Kanamycin, Streptomycin, Chloramphenicol, Tetracycline
  • Inhibition of cell$-$wall turnover (e.g. $\beta -$lactam prevents cell wall formation)
    Penicillines: e.g. Ampicillin, Amoxicillin

but still many bacterial responses to primary drug target interaction remain to be characterised.

  • An additional mechanism is the inhibition of DNA and RNA precursor synthesis. This is achieved by the antibiotics Trimethoprim and Sulfonamides.
  • A mechanism of resistance on protein level are energy dependent efflux pumps, which allows the cell to pump antibiotics that entered through porin membrane pores, out of the membrane before they can reach their target

Although having a different primary drug target interaction, all members of the three main classes affected by bactericidal antibiotics lead to free radical formation. They are extremely toxic and immediately damage DNA, proteins and membrane lipids. DNA damage then leads to SOS response via LexA-driven expression of RecA, which was verified by means of a GFP reporter (Kohanski 2007).

Radical formation is caused by quinolones, glycosides and $\beta -$lactams. They stimulate oxidation of NADH through electron transport chain (ETC), which depends on the TCA cycle. Hyperactivation of the ETC leads to formation of superoxids, which in turn mediates the Fenton reaction in cause of damaged iron-sulfur clusters that provide ferrous iron. The hydroxyl radical formation by the Fenton reaction then leads to DNA damage.


Further Reading:

  • Christopher Walsh - Antibiotics: Actions, Origins, Resistance
  • Christopher T. Walsh, Michael A. Fischbach - New Ways to Squash Superbugs. Scientific American July 2009