Antibiotics Mode of Action and Mechanisms of resistance

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Antibiotics: Mode of Action and Mechanisms of resistanceAntibiotic    Chemical substance Natural, semi synthetic and wholly synthetic Effective at low concentration (μ/ml) Bacteria static or bactericidalDr Ellabib MS Criteria for antibiotic for bacteria  Selectively toxicBactericidal (killing) Bacteriostatic (growth inhibition)  No harm to patient  Destroy structuresPresent in bacteria Not present in host Antibiotics work together with immune system M

Transcript of Antibiotics Mode of Action and Mechanisms of resistance

Antibiotics: Mode of Action and resistanceAntibiotic Chemical substance Natural, semi synthetic and wholly synthetic Effective at low concentration (/ml) Bacteria static or bactericidalDr Ellabib MS

Criteria for antibiotic for bacteria Selectively toxicBactericidal (killing) Bacteriostatic (growth inhibition) No harm to patient Destroy structures

Present in bacteria Not present in host Antibiotics work together with immune system

Minimal inhibitory concentration

Lowest level stopping growth e.g. zone of inhibition around a disk impregnated with antibiotic Antibiotics inhibit cell wall are bactericidal Without cell wall osmotic pressure cause bacteria to burst

Mode of Action Inhibitors of cell wall synthesis (Peptidoglycan) Inhibit Peptidoglycan biosynthesis at various stages Stage one: inhibit UDP N-Acetylmuramic acid through inhibition of tranferase enzyme Fosfomycin Stage two: inhibit building pentapeptides side chain through inhibition of synthetase enzyme Cycloserine Stage three: inhibit reaction leading to formation of a linear Peptidoglycan polymer (pyrophosphtase enzyme) Vancomycin & Bacitracin Stage four: preventing cross-linking and formation of Peptidoglycan (transpeptidase enzyme) Bound covalently to various proteins called penicillin binding proteins (PBPS) B-lactam antibiotics

Chemical modification changes of Blactam and their biological activity Early B-lactam antibiotics Penicillin G &V Inactive against gram negative No penetration of outer membrane Unstable to B-lactamases enzyme Active against streptococcus pyogens

Pencilliinase-resistant penicillin More stable Staphylococcus species E.g. Methicillin and Oxacillin

Aminopencillin activity against gram positive increased activity toward gram negative (E. coli) Ampicillin, Amoxil

Antipseudomonase penicillinCarboxypenicillin Increased activity against -ve and decreased activity against +ve Carbenicillin and ticarcillin Uredopenicillin Increased activity against ve and preserved activity against +ve Piperacillin and mezalocillin B-lactamases inhibitory Binds strongly to beta-lactamase Inhibit activity Called suicidal agents Clavulanic acid & Tazobactam

Cephalosporin's

First generation Old and narrow spectrum cephalosporin's Cephaloridine, Cephalexin 2nd generation -ve and some anaerobic bacteria Cefuroxime and cefoxitin 3rd generation -ve such as pseudomonas Ceftriaxone and Ceftazidime 4th generation Broad spectrum cefpime

Other B-lactam antibiotics Monobactams -ve Aztreonam Carbapenems -ve Imipenem

Antifungal Antifungal agents Chitin synthetase Polyxin and nikkomycin Glucan synthesis cilofungin

Compounds inhibit cell membrane Concentration dependent Effect integrity of CM Leakage of K, proteins and nucleic acid Disinfectants, antiseptics and polypeptides Phenols Release compounds absorbed at 200nm Inhibits electron transport chains (metabolic activity) Alcohols Interact with ester fatty acid and thiol group of proteins Used as 70% concentration

Inhibit adenosine triphosphotase (ATPase) Uptake of K+ Polymyxin B Inhibit phospholipids of ve but not +ve Antifungal agents (inhibit Ergosterol) Interact with phospholipids of CM directly Pores and leakage Amphotericin B and Nystatin Indirectly inhibit ergosterol biosynthesis Cytochrome P-450 Azoles antifungal (Miconazole, itraconazole, Clotrimazole ) Other non azoles such as terbifine morpholin and tolnaftate

Chlorohexidine

Inhibitor of protein synthesis

Mostly Bacteriostatic Selectivity due to difference in ribosome's Some toxicity eukaryotic 70S ribosome's Classes of ribosome's subunit 80s ribosome's (eukaryotic) Dissociated to 60s and 40s as Mg+ concentration Protein to RNA (50:50) 70s (prokaryotic and eukaryotic) dissociate to 30s and 50s Protein to RNA (35:65) 50-55s ribosome's (mammalian mitochondria)

Antimicrobial that bind to the 30s Amino glycosides Such as Streptomycin, gentamicin, Amikacin Gram positive and Ve Slight initial entry of the drug inside cell Interact with chain elongation (PC) at 12s Misreading of mRNA abnormal protein formation of abnormal channels Increase and irreversible entry through channels Blockage initiation of ribosome's Inhibit binding of aminoacyl-tRNA and peptide synthesis inhibit protein synthesis

Tetracycline's ( Rickettsias and mycoplasma)Short acting Chlortetracycline Intermediate Demeclocycline Long acting Doxycycline Blocking binding of aminoacyl-tRNA acceptor site on the mRNA ribosome's complex Prevent the addition of new amino acids to the growing peptide chain

Antimicrobials bound to 50s subunit

Chloramphenicol Natural antibiotic Meningitis, typhoid fever Associated with bone marrow toxicity Reversible effect Bind to a region on 50s close to site bound aminoacyl-tRNA in peptidyltransferase center Blocking addition of new amino acids Prevent growing of protein chain Inhibit peptide bound formation

Macrolides (erythromycin, claritromycin and spiramycin) +ve bacteria, mycoplasma, legionella Resistant common Stimulate dissociation of peptidy-tRNA from ribosome's during translocation step Interrupting completion of peptide chain formation

Lincosamides (Lincomycin & Clindomycin) Similar to chloramphenicol and erythromycin +ve cocci Resistant common Anaerobic bacteria

Inhibitors of protein synthesis

Fusidic acid

Bind to 70s ribosome's Active against gram positive cocci Inhibits polypeptide chain elongation

Inhibitor of nucleic acid synthesis To toxic Some are used to treat tumor, viral and serious bacterial such as TB DNA inhibition result in cell division inhibition Effect Extra chromosomal elements of DNA and plasmids Effect bacterial response to environmental changes RNA inhibition Inhibit protein synthesis

Nucleic acid inhibitors (Two groups)

Compound interfere with precursor of nucleic acid (purine, pyrimidine) Sulfonamides and trimethoprim Compounds interfere with nucleic acid synthesis at the polymerization stage

RNA polymerase inhibitors

rifampin Mycobacterium tuberculosis Inhibit DNA-dependent RNA polymeraseRNA polymerase

Minimal or core enzyme

Sigma factor (RNA)

, , 1 and subunits

Rifampin continuous Form a tight one to one complex with subunit Prevent protein synthesis (chain initiation) DNA gryases or topoisomerase inhibitors quinolones Nalidixic acid, ciprofloxacin Called nick closing enzyme Enzyme play important role in supercoil strand DNA Supercoiling is completed the single strand DNA is abolished by an enzyme that seals the nicked DNA The enzyme is known as DNA gryase or Topoisomerase 2

DNA gryase or Topoisomerase 2Four subunits and two were identified as A and A subunit introduce the nick and seal the nick they produced initially Nalidixic acid subunit Responsible for supercoil Norofloxacin & ciprofloxacin May interfere with A and subunit

Sulfonamides Trimethoprim

Inhibitors of Folic Acid Synthesis

Anti- Mycobacterial AntibioticsPara-aminosalicylic Para-aminosalicylic acid (PSA) Bacteriostatic

Dapsone Bacteriostatic

treatment of leprosy (Mycobacterium leprae)

Isoniazid (INH) bacteriostatic inhibits synthesis of mycolic acids.

Furantoin Gram positive and negative Urinary tract infection Damaging DNA Nitro-imidazole (metronidazole) Anaerobic bacteria and protozoa Reduced to Nitro radical compounds Acts as nuclease and damaging DNA Griseofulvin Antifungal agent Dermatophytes infection only Effect nuclear function Interfere with microtubules during separation of chromosomes in cell division at the metaphase

Antibiotic Mechanisms of Action

Microbial resistance to antimicrobial agents Clinical resistance By mutation or acquisition of a plasmid Provides a selective advantage Single or multiple steps

Cross resistance Vs multiple resistance Cross resistance single mutation closely related antibiotics Multiple resistance multiples mechanisms Unrelated antibiotics

Genetic basis of resistance

Mutation For the origin of some resistant variants

Acquisition Transfer of genetics material from R to S microorganism Confined by genes on Chromosomal or plasmid

Chromosomal mediated resistant Remain with the particular bacterial cell And Offspring

Plasmid mediated resistant Self replicating extra chromosomal DNA Widely distributed in nature Often transmissible Often Carry resistant determinants to many drugs

Other function of plasmid Carry genes allow bacteria to attach to mucosal surface Produce toxins Invade and colonize host cells

Transformation of plasmid resistant Conjugation (direct cell to cell contact) Transduction (bacteriophage vector) Transformation (uptake DNA from environment) Transposition (transformation via transposons

Transduction ( bacteriophages vector)

Transposons So called jumping genes Movable DNA elements Carrying resistant genes Jump or hop from plasmid to plasmid From plasmid to chromosomal Found in many bacteria Carrying resistant to many antibiotic Main cause of hospital and community outbreaks resistant

viewpoint Most important type of resistant Transmissible Usually highly stable Convert resistant to different class of antibiotics Often associated with other characteristics Requirements for antibiotic activity and mechanisms resistant

Plasmid from Epidemiological

Properties of antibiotic required for efficacy Penetration to target site in sufficient amount Evade inactivation enzymes by microorganism Interaction with target molecules to initiate an effect

Steps of re