Antibiotics Affecting DNA PDF

Antibiotics affecting nucleic acid synthesis Inhibitors of nucleic acid synthesis The presence of differences between enzymes that carry out the synthesis of nucleic acids in eukaryotic and prokaryotic cells allow antibiotics to target these processes in bacterial pathogens. 1. Fluor...

Antibiotics affecting nucleic acid synthesis Inhibitors of nucleic acid synthesis The presence of differences between enzymes that carry out the synthesis of nucleic acids in eukaryotic and prokaryotic cells allow antibiotics to target these processes in bacterial pathogens. 1. Fluoroquinolones : Quinolones are potent antimicrobial agents with a basic chemical structure of bicyclic ring. Fluorine atom at position C-6 and various substitutions on the basic quinolone structure yielded fluoroquinolones, The fluoroquinolone antibiotics include ciprofloxacin , gemifloxacin , levofloxacin , moxifloxacin , and ofloxacin , norfloxacin. Mechanism of action They block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase ) against gram negative and topoisomerase IV against gram positive Spectrum of activity : Quinolones are considered bactericidal agents Active against gram negative bacteria as pseudomonas specially ciprofloxacin gram positive except MRSA active against mycoplasma Chlamydia and mycobacterium tuberculosis Newer fluoroquinolones have reliable activity against streptococci (including Streptococcus pneumoniae with reduced penicillin sensitivity) and some anaerobes; moxifloxacin in particular is active against most clinically significant obligate anaerobes. Oral absorption is diminished by coadministration of polyvalent cations (aluminum, magnesium, calcium, zinc, and iron preparations). After oral and parenteral administration, fluoroquinolones are widely distributed in most extracellular and intracellular fluids and are concentrated in the prostate, lungs, and bile. Side effects Fluoroquinolones are generally very safe antibiotics which do not cause serious or life-threatening adverse reactions. The most frequent side-effects are gastrointestinal reactions (nausea, dyspepsia, vomiting) and CNS reactions such as dizziness, insomnia and headache. The finding in juvenile animals of cartilage damage after administration of high doses have resulted in recommendations that fluoroquinolones should not be used in children. Serious adverse effects of fluoroquinolones are uncommon; main concerns include the following: Upper gastrointestinal adverse effects CNS adverse effects (eg, mild headache, drowsiness, insomnia, dizziness, mood alteration). Seizures are rare, but fluoroquinolones should not be used in patients with CNS disorders. Peripheral neuropathy may occur soon after taking the drug and may be permanent.. Tendinopathy, including rupture of the Achilles tendon, may occur even after short-term use of fluoroquinolones. ventricular arrhythmias and sudden cardiac death. Coumarins. The coumarins, such as coumermycin A and novobiocin, are antibiotics that inhibit certain DNA topoisomerases, enzymes that catalyze interconversions of different topological isomers of DNA. One of the topoisomerases that the coumarins inhibit is bacterial DNA gyrase. Novobiocin is a member of the aminocoumarin antibiotic class produced by Streptomyces niveus Actinobacteria which inhibit the bacterial DNA synthesis process. Novobiocin binds with the GyrB subunit of the DNA gyrase enzyme and inhibits the DNA transcription process. It is also found to inhibit the action of DNA topoisomerase IV. It was initially proposed as an antibiotic to treat the infections caused by Gram-positive cocci. In 1964, it was approved as an indicated treatment option to treat the infections of Staphylococcus aureus if other antibiotics were resistant; however, due to its toxicity and lower effectiveness, in 2009 the FDA put a ban on its use as a treatment measure. Although novobiocin is not used for treatment, it is still used in clinical laboratories in the Novobiocin Susceptibility Test for the identification and differentiation of Staphylococcus spp. Acquired resistance to novobiocin in staphylococci and bacteria of other genera is predominantly due to the accumulation of point mutations in the gene gyrB, encoding the DNA gyrase B subunit (GyrB), the target of novobiocin Novobiocin is used occasionally as an alternative to penicillins against penicillin-resistant Staphylococcus spp. It has synergistic activity with tetracyclines, and combination novobiocin–tetracycline therapy has been used in an attempt to broaden the spectrum of activity and decrease the development of resistance. Rifamycins Ex: Rifampin. Rifapentine. Rifaximin. Rifabutin. Mechanism of action: It inhibits RNA synthesis by binding to and inhibiting an enzyme called RNA polymerase. This enzyme transfers the instructions carried by genes to the intermediary molecule, mRNA. Interference in this process ultimately stops new proteins being made. Spectrum of activity : It is one of the most potent and broad-spectrum antibiotics against bacterial pathogens. rifamycins are the cornerstone of modern therapy for active tuberculosis and are extremely effective in the treatment of latent Mycobacterium tuberculosis infection Non tuberculosis spectrum Staphylococcus spp.(including aureus), Streptococcus spp.(including S. pneumoniae), Legionella spp., Neisseria meningitides, Bacterial resistance to rifampin it is caused by mutations leading to a change in the structure of the beta subunit of RNA polymerase. a large number of RNA polymerases with various degrees of sensitivity to rifampin have been found. Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, fidaxomicin demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. Inhibitors of metabolic reactions Antibiotics that disrupt essential bacterial metabolic pathways are acting as antimetabolites. These chemicals are structurally similar to natural metabolites but just different enough to interfere with normal cell function. Anti folate drugs 1. Sulfonamide the sulfonamides are bacteriostatic inhibitors of folic acid synthesis As anti metabolites of para amino benzoic acid (PABA) , they are competitive inhibitors of dihydropteroate synthase The selective toxicity of sulfonamides results from the inability of mammalian cells to synthesize folic acid they must use performed folic acid that is present in diet 2.trimethoprim inhibits the synthesis of folic acid, a vitamin which bacteria, unlike humans, must make themselves. Trimethoprim is a structural analogue of dihydrofolic acid, an intermediate compound in the folic acid pathway. Trimethoprim out-competes dihydrofolic acid to react with a specific bacterial enzyme in the pathway, thereby interrupting folic acid synthesis and inhibiting bacterial growth Examples of sulfonamides includes sulfadiazine, sulfamethizole , sulfamethoxazole , sulfasalazine , sulphacetamide Spectrum of activity : The spectrum of all sulfonamides is generally the same. Sulfonamides inhibit both gram-positive and gram-negative bacteria, Nocardia, Actinomyces spp, and some protozoa such as coccidia and Toxoplasma spp. combination Trimethoprim/sulfamethoxazole, also known as co-trimoxazole among other names, is an antibiotic used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazole. Resistance Bacteria resistant to sulfa drugs often have mutations in the DHPS enzyme. Metronidazole( flagyl) Mechanism of action It diffuses into the organism, inhibits protein synthesis by interacting with DNA and causing a loss of helical DNA structure and strand breakage. Therefore, it causes cell death in susceptible organisms. Side effects: Bacterial resistance Metronidazole resistance can occur by a number of different mechanisms that involve reduced uptake of the drug, increased removal from the bacterial cell or by reducing the rate of metronidazole activation inside anaerobes