Antibiotics Inhibiting Nucleic Acid Synthesis

ANTIBIOTICS INHIBITING NUCLEIC ACID SYNTHESIS Antibioticare a groupcompound, whether natural or synthetic, which has the effect of suppressing or stopping a processbiochemistryin theorganism, especially in the processinfectionbybacteria. Antibiotics can be classified based on their spectrum or range of action, mechanism of action, producing strain, method of biosynthesis or based on their biochemical structure. Based on the spectrum or range of action, antibiotics can be divided into narrow spectrum antibiotics and broad spectrum antibiotics. Narrow spectrum antibiotics are only able to inhibit certain types of bacteria, for example they are only able to inhibit or kill gram-negative or grampositive bacteria. Meanwhile, broad spectrum antibiotics can inhibit or kill grampositive and gram-negative bacteria. Based on the mechanism of action, antibiotics are divided into five: Antibiotics with a mechanism for inhibiting cell wall synthesis Plasma membrane damage Inhibition of protein synthesis Inhibition of nucleic acid synthesis Inhibition of the synthesis of essential metabolites. Antibiotics are used to treat various types of infections caused by germs or also to prevent infections, for example in major surgery. It is also given prophylactically to patients with artificial joints and heart valves, also before tooth extraction. Inhibition of nucleic acid synthesis takes the form of inhibition of transcription, replication of microorganisms. Antibiotics that inhibit nucleic acid synthesis include quinolone antibiotics and rifampin or rifampicin. Antibiotics that inhibit nucleic acid (DNA/RNA) synthesis a. Quinolones Quinolones are bactericides because they inhibit the release of open DNA strands in the supercoiling process by inhibiting DNA gyrase (an enzyme that forces bacterial DNA to become supercoiled). To insert long double-stranded DNA into bacterial cells, the DNA is arranged in loops (relaxed DNA) which are then shortened by the supercoiling process. Eukaryotic cells do not contain DNA gyrase. Important properties of Quinolones are their good penetration into tissues and cells (compare with Penicillin), their effectiveness when administered orally, and their relatively low toxicity. During the reproduction of germs there is something called replication and transcription where the double helix of the germ DNA separates into 2 strands of DNA. This separation will always cause excessive twisting of the DNA double helix before the split point. This mechanical barrier can be overcome by germs with the help of the DNA gyrase enzyme. The role of quinolone antibiotics is to inhibit the action of the DNA gyrase enzyme on germs and is bactericidal, so the germs die. Side Effects and Drug Interactions The quinolone class of antibiotics is generally well tolerated. The most important side effects are on the gastrointestinal tract and central nervous system. Gastrointestinal manifestations, especially nausea and loss of appetite, are the most frequently encountered side effects. Side effects on the central nervous system are generally mild in the form of headaches, vertigo and insomnia. More serious side effects of Quinolones such as psychosis, hallucinations, depression and seizures are rare. Elderly patients, especially those with arteriosclerosis or epilepsy, are more likely to experience this side effect. Enoxacin inhibits the metabolism of Theophylline and may cause increased Theophylline levels. Ciprofloxacin and several other quinolones also show this effect, although it is not as dramatic. Clinical Use Urinary tract infections such as prostatitis, urethritis, cervicitis and pyelonphritis. Gastrointestinal infections such as typhoid and paratyphoid fever Lower respiratory tract infections such as bronchitis, pneumonia, sinusitis, diseases transmitted through sexual contact, gonorrhea Examples of quinolone drugs: 1) Nalidixic Acid Nalidixic Acid was the first quinolone found to have antibacterial activity, but Nalidixic Acid does not reach systemic antibacterial levels and to date has only been used in urinary tract infections. Fluoroquinolones Work mechanism Inhibits bacterial DNA replication by interfering with the work of topoisomerase II during bacterial growth and reproduction Antimicrobial spectrum All fluoroquinolones are bactericidal. In general, it is effective against gram-negative organisms. Although active against some gram-positive organisms, fluoroquinolones should not be used in the treatment of pneumococcal or enterococcal infections. Fluoroquinolones reduce the incidence of postoperative urinary tract infections. Examples of fluoroquinolone drugs Ciprofloxacin: this drug is the most potent fluoroquinolone and has the same antibacterial spectrum as norfloxacin. Ciprofloxacin is useful in the treatment of pseudomonas infections in cystic fibrosis. Ciprofloxacin can work synergistically with β-lactam drugs. Norfloxacin: this drug is effective against gram-negative and gram-positive organisms in the treatment of urinary tract infections and prostatitis, but is not effective in systemic infections Ofloxacin: like norfloxacin, ofloxacin is mainly used in the treatment of prostatitis caused by E.coli and sexually transmitted diseases except syphillis. Ofloxacin can be used as an alternative therapy for gonorrhea sufferers. Lomefloxacin: useful in the treatment of urinary tract infections and bronchitis. Lomefloxacin is not effective against pseudomonas bacteremia Resistance Altered targets : Modifications to DNA-gyrase, particularly to the amino acids of the N-terminus of the A subunit, have led to decreased affinity for fluoroquinolones. The B gyrase subunit rarely undergoes mutations Reduced accumulation: reduced drug concentration in bacterial cells is related to two mechanisms. One involves a reduction in the number of porin proteins in the outer membrane of resistant cells, thereby interfering with drug entry into intracellular gyrase. Another mechanism is related to the efflux mechanism in the cytoplasmic membrane Pharmacokinetics Absorption: taking fluoroquinolone drugs together with sucralfate, antacids containing aluminum or magnesium or additional foods containing iron or zinc can interfere with the absorption of antibacterial drugs Distribution: All fluoroquinolones distribute well into all body tissue fluids. Levels are high in bones, urine, kidneys, and prostate tissue (but not in prostate fluid). Fluoroquinolones accumulate in macrophages and polymorphonuclear leukocytes, making them effective against intracellular organisms. Metabolism: these drugs are partially metabolized into compounds that lack antimicrobial activity Excretion: the original drug and its metabolites are excreted in the urine and high concentrations occur here. This is the primary excretion route for ofloxacin. Renal failure prolongs the half-life of each drug. Other fluoroquinolones experience hepatic and renal clearance. The half-life of fluoroquinolones ranges from 3-5 hours except lomefloxacin which has a half-life of 8 hours. b. Rifampicin Rifampicin is an antibiotic drug used to treat bacterial infections. Rifampicin is often used to treat tuberculosis (TB). This drug can also be used to prevent infection after coming into contact with someone who is suffering from a serious infection. This medicine is only given with a doctor's prescription. Soft tissue and bone infections. Like Osteomyelitis. For post-surgical infections by enterococcus bacteria Ps. aeroginosa or staphylococci that are resistant to Beta Lactams or Aminoglycosides. Rifampicin mechanism of action Rifampicin works by killing the bacteria that cause infections. The way this drug works is by deactivating a bacterial enzyme called RNA polymerase. Bacteria use RNA polymerase to make proteins and to copy their own genetic information (DNA). Without this enzyme bacteria cannot reproduce and the bacteria will die. Drug action is bactericidal, can kill semi-dormant germs that cannot be killed by isoniazid. Mechanism of action, based on specific inhibition of the bacterial enzyme Ribose Nucleotide Acid (RNA)-polymerase so that RNA synthesis is disrupted. Drug Interactions The interactions of this drug are to speed up the metabolism of methadone, reduce absorption by antacids, speed up metabolism, reduce plasma levels of dizopyramide, mexiletine, propanone and quinidine, speed up the metabolism of chloramphenicol, nicumalone, warfarin, estrogen, theophylline, thyroxine, tricyclic anti-depressants, anti-diabetics (reduces efficacy chlorpropamide, tolbutamide, sulfonyl urea), phenytoin, dapsone, floconazole, itraconazole, ketoconazole, terbinafine, haloperidol, indinafir, diazepam, atofaquone, betablocker(propanolol), diltiazem, nifedipine, verapamil, cyclosprosin, reduces the efficacy of cardiac glucosides, reduces the effect of corticosteroids, flufastatin. Rifampicin is a potent enzyme inducer of cytochrome P-450 isoenzymes, resulting in decreased serum concentrations of drugs metabolized by these isoenzymes. These drugs may need to be increased during TB treatment, and reduced again 2 weeks after Rifampicin is stopped. Interacting drugs: include: protease inhibitors, macrolide antibiotics, levothyroxine, norethindrone, warfarin, cyclosporine, phenytoin, verapamil, diltiazem, digoxin, nortriptyline, alprazolam, diazepam, midazolam, triazolam and several other drugs. Side effects In the Gastrointestinal Tract; heartburn, epigastric pain, nausea, vomiting, anorexia, bloating, stomach cramps, diarrhea, CNS: fatigue, drowsiness, headache, ataxia, confusion, dizziness, inability to think, general numbness, pain in the limbs, loose muscles, visual impairment, temporary low frequency deafness (rare). Hypersensitivity: fever, pruritis, urticaria, skin eruptions, oral and tongue ulcers, eosinophilia, hemolysis, hemoglobinuria, hematuria, renal insufficiency, acute renal failure (reversible). Hematology: thrombocytopenia, transient leukopenia, anemia, including hemolytic anemia. Other intoxications: Hemoptysis, low chain proteinurea, menstrual disorders, hematoreal syndrome. CONCLUSION From the results of the discussions that have been carried out, it can be concluded that: Antibiotics that inhibit nucleic acid synthesis include quinolone antibiotics, fluoroquinolones and rifampicin. The role of quinolone antibiotics is to inhibit the action of the DNA gyrase enzyme on germs and is bactericidal, so the germs die. Fluoroquinolones inhibit bacterial DNA replication by interfering with the work of topoisomerase II during bacterial growth and reproduction. Rifampicin works by killing the bacteria that cause infections. The way this drug works is by deactivating a bacterial enzyme called RNA polymerase. Bacteria use RNA polymerase to make proteins and to copy their own genetic information (DNA).