Glycopeptides, Polypeptides and Lipopeptides

Glycopeptides Glycopeptides, Vancomycin  Originally obtained from Streptomyces  Disrupts cell wall peptidoglycan synthesis in growing grampositive bacteria (interacts with the D-alanine-D-alanine termini)  Vancomycin is inactive against gram-negative bacteria  Some organisms are intrinsically resistant to vancomycin Leuconostoc, Lactobacillus, Pediococcus, and Erysipelothrix Inhibition of Cell Wall Synthesis Polypeptides Polypeptides, Bacitracin  Bacillus  Interfering with dephosphorylation and recycling of lipid carrier  It may also damage the bacterial cytoplasmic membrane  Used in creams, ointments, sprays Treatment of skin infections caused by gram-positive bacteria  (Staphylococcus and group A Streptococcus)  Gram-negative bacteria are resistant to this agent Polypeptides, polymyxins  Cyclic polypeptides  Derived from Bacillus polymyxa  Interacting with lipopolysaccharides and phospholipids in outer membrane and increased cell permeability  Polymyxin Band E (colistin) are capable of causing serious nephrotoxicity Polypeptides, polymyxins  localized infections such as External otitis, eye infections, and skin infections  Oral administration is used to sterilize the gut  Are most active against gram-negative bacilli Some organisms such as Acinetobacter and Pseudomonas are only susceptible to colistin Inhibition of Cell Wall Synthesis Lipopeptides Lipopeptides, Daptomycin  Binds irreversibly to cytoplasmic membrane, resulting in membrane depolarization.  Potent activity against gram-positive bacteria, but gram-negative bacteria are resistant to daptomycin.  Daptomycin has good activity against multidrug-resistant staphylococci, streptococci, and enterococci (including vancomycin-resistant strains. Isoniazid, Ethionamide, Ethambutol, and Cycloserine  Are cell wall-active antibiotics used for the treatment of mycobacterial infections  Isoniazid (isonicotinic acid hydrazide [INH]) Bactericidal against actively replicating mycobacteria The synthesis of mycolic acid is affected Isoniazid, Ethionamide, Ethambutol, and Cycloserine Ethionamide  Derivative of INH  Blocks mycolic acid synthesis  Interferes with synthesis of arabinogalactan in the cell wall Cycloserine inhibits  D-alanine-Dalanine synthetase  Alanine racemase Resistance to four antibiotics results from reduced drug uptake into bacterial cell or alteration of target sites Other Antibiotics Pyrazinamide (PZA)  The active form of this antibiotic is pyrazinoic acid produced when PZA is hydrolyzed in the liver  Is active against M. tuberculosis at a low pH such as that found in phagolysosomes  The mechanism is unknown Inhibition of Protein Synthesis Basic Mechanisms of Antibiotic Action Aminoglycosides 30S  Amino sugars linked to an aminocyclitol ring The structure of streptomycin Aminoglycosides 30S  Streptomycin, Neomycin, Kanamycin, and Tobramycin Streptomyces species  Gentamicin and Sisomicin Micromonospora species Amikacin from kanamycin  Synthetic derivatives Netilmicin from sisomicin Aminoglycosides 30S  Irreversibly binding to the 30S ribosomal proteins 1- Production of aberrant proteins as the result of misreading of the messenger RNA (mRNA) 2- interruption of protein synthesis by causing the premature release of the ribosome from mRNA  The aminoglycosides are bactericidal Aminoglycosides 30S  Used to treat serious infections caused by many gram-negative bacilli and some gram-positive organisms Enterobacteriaceae and Pseudomonas species  Anaerobes are resistant to aminoglycosides Penetration through the cytoplasmic membrane is an aerobic, energy-dependent process  Gentamicin and tobramycin both of which have a broad spectrum of activity Aminoglycosides 30S Resistance 1- Alteration of bacterial ribosome is relatively uncommon Except in members of the genus Enterococcus 2- Inhibition of transport of antibiotic into the bacterial cell Pseudomonas , anaerobic bacteria 3- Enzymatic modification of aminoglycosides by phosphorylation, adenylation, and acetylation of amino and hydroxyl groups of antibiotic the most common mechanism of resistance Tetracyclines 30S Tetracyclines  Broad-spectrum  Bacteriostatic Binding reversibly to the 30S ribosomal subunits  Blocking binding of aminoacyltransfer RNA (tRNA) to 30S ribosome-mRNA complex Tetracyclines 30S Tetracyclines Tetracycline, Doxycycline, Minocycline Chlamydia Mycoplasma Rickettsia Other selected gram-positive and gram-negative bacteria Tetracyclines 30S Resistance 1- Decreased penetration of antibiotic into bacterial cell 2- Active efflux of antibiotic out of the cell 3- Alteration of ribosomal target site 4- Enzymatic modification of antibiotic Mutations in chromosomal gene encoding outer membrane porin protein, OmpF, can lead to low-level resistance to tetracyclines, as well as to other antibiotics (e.g., ,B-Iactams, quinolones, chloramphenicol) Glycylclines 30S Tigecycline Semisynthetic derivative of minocycline Broad spectrum of activity against gram-positive, gramnegative, and anaerobic bacteria, although Proteus, Morganella, Providencia, and P. aeruginosa are generally resistant. Mutations in chromosomal gene encoding outer membrane porin protein, OmpF, can lead to low-level resistance to tetracyclines, as well as to other antibiotics (e.g., ,B-Iactams, quinolones, chloramphenicol) Macrolides 50S Macrolides  Basic structure is a macrocyclic lactone ring bound to two sugars, desosamine and cladinose  Bacteriostatic  Broad spectrum  Blocks polypeptide elongation by reversible binding to 50S ribosome  Erythromycin, derived from Streptomyces erythreus Azithromycin Clarithromycin Macrolides 50S  Used to treat pulmonary infections caused by Mycoplasma, Legionella, and Chlamydia species  Infections caused by Campylobacter species Gram-positive bacteria in patients allergic to penicillin Macrolides 50S Resistance 1- Alteration of ribosomal target site methylation of 23S ribosomal RNA, prevents binding by antibiotic 2- Enzymatic modification of the antibiotic Destruction of the lactone ring by an erythromycin esterase 3- The active efflux of the antibiotic from the bacterial cell Ketolides 50S Telithromycin Semisynthetic derivatives of erythromycin, modified to increase stability in acid. Treatment of community-acquired pneumonia. It is active against S. pneumoniae, Legionella, Mycoplasma, and Chlamydia Oxazolidinones 50S Oxazolidinones  Linezolid, Tedizolid  Narrow-spectrum  Block initiation of protein synthesis interfering with formation of initiation complex at 50S ribosomal subunit Chloramphenicol 50S Chloramphenicol  Broad spectrum  Bacteriostatic  Only for treatment of typhoid fever  Blocking peptide elongation Binding reversibly to peptidyl transferase in 50S ribosomal subunit  Disrupts protein synthesis in human bone marrow cells and can produce aplastic anemia (1 per 24,000 treated patients) Chloramphenicol 50S Resistance 1- Enzymatic modification of antibiotic Chloramphenicol acetyl transferase Plasmid 2- Mutations in chromosomal gene encoding, OmpF Less commonly Causing gram-negative bacilli to be less permeable lincosamide 50S Clindamycin  is a derivative of lincomycin originally isolated from Streptomyces lincolnensi  Blocks protein elongation  Inhibits peptidyl transferase by interfering with binding of amino acid-acyl-tRNA complex by binding to the 50S ribosome lincosamide 50S Clindamycin Active against Staphylococci Inactive against Anaerobic gram-negative bacilli Aerobic gram-negative Resistance Methylation of the 23S ribosomal RNA Streptogramin 50S Streptogramin  Are a class of cyclic peptides produced by Streptomyces species  Group A and group B act synergistically to inhibit protein synthesis  Quinupristin-dalfopristin (trade name Synercid) Streptogramin 50S Dalfopristin  Prevents peptide chain elongation By binds to the 50S ribosomal subunit induces a conformational change that facilitates binding of quinupristin Quinupristin  Initiates premature release of peptide chains from the ribosome Quinupristin-dalfopristin active against Staphylococci, streptococci, and E. faecium (but not E. faecalis) 64 Basic Mechanisms of Antibiotic Action Inhibition of Nucleic Acid Synthesis; Quinolones Quinolones Synthetic Inhibit bacterial DNA gyrases or topoisomerases Nalidixic acid Fluoroquinolones Ciprofloxacin Levofloxacin Gatifloxacin Inhibition of Nucleic Acid Synthesis; Quinolones Nalidixic acid  Treat urinary tract infections caused by a variety of gram-negative bacteria Fluoroquinolones  Made by modifying the two ring quinolone nucleus  Have excellent activity against gram-positive and gram-negative Inhibition of Nucleic Acid Synthesis; Quinolones Resistance 1- Alteration of the antimicrobial target site Alteration of α subunits  DNA gyrase 2α + 2β subunits  Quinolones binding to the α subunits 2-Decreased drug uptake Changes in porin proteins on the bacterial surface Resistance can develop rapidly in Pseudomonas, oxacillin-resistant staphylococci, and enterococci Inhibition of Nucleic Acid Synthesis; Rifampin Rifampin A semisynthetic derivative of rifamycin B produced by Streptomyces mediterranei Inhibits the initiation of RNA synthesis By binds to DNA dependent RNA polymerase  Bactericidal  Very active against Mycobacterium tuberculosis Staphylococci Streptococci Inhibition of Nucleic Acid Synthesis; Rifampin Resistance  Gram-positive bacteria a mutation in the chromosomal gene that codes for the β subunit of RNA polymerase  Gram negative bacteria are resistant intrinsically to rifampin decreased uptake of the hydrophobic antibiotic Inhibition of Nucleic Acid Synthesis; Metronidazole Metronidazole  Reduction of its nitro group by bacterial nitroreductase Producing cytotoxic compounds that disrupt the host DNA  Anaerobic bacterial infections ( B. fragilis) Resistance 1- Decreased uptake of antibiotic 2- Elimination of cytotoxic compounds before they can interact with host DNA Inhibition of Nucleic Acid Synthesis; Clofazimine Clofazimine  Is a lipophilic antibiotic that binds to mycobacterial DNA  Is highly active against M. tuberculosis  Is a first-line drug for the treatment of Mycobacterium leprae infections Basic Mechanisms of Antibiotic Action Antimetabolites Sulfonamides  Preventing the synthesis of the folic acid  Compete with p-aminobenzoic acid  Mammalian organisms do not synthesize folic acid Treatment of Nocardia, Chlamydia, and some protozoa infections Sulfacetamide Sulfadiazine Sulfamethoxazole R Group 74 Antimetabolites Trimethoprim  Inhibiting dihydrofolate reductase  Preventing the conversion of dihydrofolate to tetrahydrofolate  Blocks the formation of thymidine, some purines, methionine, and glycine  Trimethoprim + sulfamethoxazole: Synergistic combination Treatment of acute and chronic urinary tract infections Antimetabolites  Dapsone and p-aminosalicylic acid are also antifolates useful for treating mycobacterial infections Resistance 1- Decreased affinity of dihydrofolate reductase: trimethoprim resistance 2- Use exogenous thymidine are also intrinsically resistant enterococci Antibacterial Agents  Inhibition of Cell wall Synthesis Penicillins Beta-Lactam Antibiotics Glycopeptide Antibiotics Bacitracin Cycloserine Penicillin G, V- Cephalosporins Oxacillin, Ampicillin Cephalexin, Cefamandole, cefotaxime, cefepime Cephamycins Cefmetazole, Cefoxitin Carbapenems Imipenem, Meropenem Monobactams Aztreonam Teicoplanin, Vancomycin Antibacterial Agents Aminoglycosides (initiation inhibitors) 30 s Tetracycline (tRNA binding)  Inhibition of Protein Synthesis -mycin -micin Kanamycin (Amikacin, Arbekacin, Tobramycin) Gentamicin (Micromonospora) (Netilmicin, Sisomicin ) Tetracyclines Doxycycline Glycylcyclines Tigecycline (Streptomyces) Oxazolidinone (initiation inhibitors) Amphenicols (peptidyl transferase) 50s MLS (transpeptidation) Streptomycin , Neomycin, Linezolid Chloramphenicol Macrolides Erythromycin Azithromycin Lincosamides Clindamycin Lincomycin Pristinamycin Streptogramins 78 Quinupristin/dalfopristin Antibacterial Agents Quinolone Rifampin  Inhibition of Nucleic Acid Synthesis inhibit bacterial DNA gyrases or topoisomerases Nalidixic acid ciprofloxacin, levofloxacin inhibits the initiation of RNA synthesis Rifabutin Metronidazole Producing cytotoxic compounds that disrupt the host DNA Antibacterial Agents  Antimetabolites Sulfonamides preventing the synthesis of the folic acid required by compete with p-aminobenzoic acid Trimethoprim inhibiting dihydrofolate reductase, thereby preventing the conversion of dihydrofolate to tetrahydrofolate