Antimicrobial agents mechanisms of action and resistance
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İ. Çağatay Acuner M.D., Clinical Microbiologist, Associate Professor Department of Microbiology Faculty of Medicine , Yeditepe University , Istanbul [email protected] Antimicrobial agents : mechanisms of action and resistance.

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Antimicrobial agents mechanisms of action and resistance

İ. Çağatay Acuner M.D., Clinical Microbiologist, Associate Professor

Department of MicrobiologyFaculty of Medicine, Yeditepe University, Istanbul

[email protected]

Antimicrobial agents:mechanisms of action and resistance


Global sorun antibiyotik direnci who 2011 d nya sa l k g n temas

Global Sorun: Antibiyotik Direnci (WHO, 2011, Dünya Sağlık Günü Teması)


Antibiotic resistance challenge

Antibiotic resistance challenge


Antibiotic resistance challenge1

Antibiotic resistance challenge


Antibiotic resistance challenge2

Antibiotic resistance challenge


Temel terminoloji

Temel Terminoloji

  • Antibiyotik: Canlı organizmalardan elde edilmiş (geçmişte; günümüzde sentetik dahil) ve (genellikle) bakteriyel infeksiyonların tedavisinde kullanılan maddelerdir.

  • Antimikrobiyal: Bakteri, mantar, protozoon, virus gibi mikroorganizmaların üremesini durduran (statik) veya öldüren (sidal) maddelerdir. (Dezenfektan; cansız nesnelere veya vücut-dışı kullanılan)

    • Antibakteriyel, antiviral, antifungal, antiparazitik


Temel terminoloji1

Temel Terminoloji

  • Duyarlı: İnfeksiyon bölgesi için önerilen doz kullanıldığında, antimikrobiyal ajanın genellikle erişilebilir konsantrasyonları ile bakteriyel izolatlar inhibe edilir.

  • Dirençli (doğal dirençli, kazanılmış dirençli): İnfeksiyon bölgesi için önerilen doz kullanıldığında, antimikrobiyal ajanın genellikle erişilebilir konsantrasyonları ile bakteriyel izolatlar inhibe edilmez; ve/veya; inhibe olduğu zon çapı veya MİK değeri, spesifik direnç mekanizmalarının olabileceği kırılma-noktası aralığına (örn. beta-laktamazlar) düşer ve ajanın bakteriyel izolata karşı etkinliği klinik olarak tedavi araştırmalarında güvenilir olarak gösterilememiştir.

  • Orta duyarlı: Ajanın genellikle erişebildiği kan ve doku MİK düzeylerine karşı duyarlı izolatlara kıyasla klinik yanıtın daha az olduğu bakteriyel izolatlar için kullanılır. Droğun fizyolojik olarak konsantre olduğu kompartmanlarda etkili olabilir (örn. idrarda kinolon ve beta-laktamlar). Ayrıca, dar farmakotoksisite marjini olan droglar için, küçük, kontrol edilemeyen teknik faktörlerin, sonuç yorumunda majör uyumsuzluğa neden olmaması için bir tampon aralığıdır.

  • Çoklu-dirençli (MDR): ≥ x2 kimyasal sınıf; farklı tanımlamalar var!

  • Aşırı-dirençli (XDR): XDR-TB (R ≥INH+RMP+FQ+AG)

  • Pan-drog dirençli (PDR): tartışmalı tanım önerileri var!


Temel terminoloji2

Temel Terminoloji


Outline

Outline

  • General features of antimicrobials

  • Classification of antimicrobialsbased on mechanisms of effectandresistancemechanisms

    • Inhibition of cell-wallsynthesis

    • Increase in cell-membranepermeability

    • Inhibition of protein synthesis

    • Inhibition of nucleicacidsynthesis

    • Antimetabolites


Terminology

Terminology


Past present and future

Past, Present, and Future

  • Topical antisepticswereineffective against systemic bacterial infections.

  • In 1935, the dye prontosil was shown to protect mice against systemic streptococcal infection and to be curative in patients suffering from such infections.

  • It was soon found that prontosil was cleaved in the body to release p-aminobenzenesulfonamide (sulfanilamide), which was shown to have antibacterial activity.

  • This first "sulfa" drug started a new era in medicine; chemotherapy


Past present and future1

Past, Present, and Future

  • Compounds produced by microorganisms (antibiotics) were discovered that inhibit the growth of other microorganisms

  • Alexander Fleming was the first to realize the mold Penicillium prevented the multiplication of staphylococci.

  • Streptomycin and the tetracyclines were developed in the 1940s and 1950s

  • Aminoglycosides, semisynthetic penicillins, cephalosporins, quinolones, and other antimicrobials followed.

  • All these antibacterial agents greatly increased the range of infectious diseases that could be prevented or cured.

  • Although the development of new antibacterial antibiotics has lagged in recent years, some new classes of agents have been introduced:ketolides (e.g., telithromycin), glycylcyclines (tigecycline), lipopeptides (daptomycin), streptogramins (quinupristin-dalfopristin), and oxazolidinones (linezolid).

  • Unfortunately, with the introduction of new chemotherapeutic agents, bacteria have shown a remarkable ability to develop resistance.

  • Thus antibiotic therapy is only one weapon, against infectious diseases.

  • As resistance to antibiotics is not predictable, physicians must rely on local surveillance (epidemiological) data and guidelines for the initial selection of empirical therapy.


Antibiotics

Antibiotics

  • Toxic for the microorganismal agent

  • In host,

    • non-toxic, or

    • tolerable toxicity

  • The effects of this selective toxicity in microorganism;

    • Inhibition of growth (bacteriostatic), or

    • Death (bactericidal)


  • Antibiotics1

    Antibiotics

    • Bacteriostaticeffect is sufficient in most of thepatients

    • Afterinhibition of growth, immunesystemeliminatesthebacteria

    • However;

      • Inimmunodeficientpatients, or

      • Inseriousinfectionssuch as, endocarditis, meningitis, etc. bactericidaleffect is required


    Antibiotics2

    Antibiotics

    • Usually, the effect of antibiotics on bacteria occur by more than one mechanism

      • An antimicrobial agent that distrupts the cell-wall synthesis may also distrupt the protein or nucleic acid synthesis at certain concentration level

    • However, usually, one of these mechanisms is more important than others


    Mechanisms of antimicrobial effect

    Mechanisms of antimicrobial effect

    • Inhibition of cell-wall synthesis

    • Increase in cell-membrane permeability

    • Inhibition of protein synthesis

    • Inhibition of nucleic acid synthesis

    • Antimetabolites


    Cell wall in bacteria

    Cell-wall in bacteria


    Cell wall in bacteria1

    Cell-wall in bacteria


    Antimicrobials that act by cell wall inhibition

    Antimicrobials that act by cell-wall inhibition

    • Beta-lactams;

      • Penicillins;

        • Natural penicillins; penicillin G, penicillin V

        • Aminopenicillins; ampicillin, amoxicillin

        • Anti-stafilococcal penicillins; methicillin, nafcillin, oxacillin

        • Anti-pseudomonal penicillins; carbenicillin, ticarcillin, ureidopenicillins ( piperacillin)

        • β-Lactam with β-lactamase inhibitor (combination)

          • ampicillin-sulbactam,

          • amoxicillin-clavulanate,

          • ticarcillin-clavulanate,

          • piperacillin-tazobactam

      • Cephalosporins and Cephamycins;

        • First generation (narrow spectrum) ; cephalexin, cephalothin, cefazolin, cephapirin, cephradine

        • Second generation (expanded-spectrum); cefaclor, cefuroxime

        • Expanded-spectrum cephamycins ; cefotetan, cefoxitin

        • Third generation (broad spectrum); cefixime, cefotaxime, ceftriaxone, ceftazidime, cefoperazon

        • Fourth generation (extended spectrum); cefepime, cefpirome

      • Monobactams; aztreonam

      • Carbapenems; imipenem, meropenem, ertapenem


    Antimicrobials that act by cell wall inhibition1

    Antimicrobials that act by cell-wall inhibition

    • Glycopeptides; vancomycin, teicoplanin

      • Bactericidal for bacteria in exponential growth

        • Effective on Gr (+)s

      • Some Gr (+)s are resistant intrinsically

        • Lactobacillus

        • Pediococcus

        • Leuconostoc

    • Phosfomycin

      • inactivates the enzyme UDP-N-actetylglucosamine-3-enolpyruvyltransferase

      • NAM production from NAG is blocked in the cytoplasm and cell-wall synthesis is impaired

    • Ethionamide

    • Bacitracin

    • Isoniazid


    Antimicrobials that act by cell wall inhibition2

    Antimicrobials that act by cell-wall inhibition

    • Cycloserine;

      • Analogue of D-alanine

      • D-alanine-D-alanine bond is prevented; so, production of cell-wall precursor is avoided

      • Highly toxic

      • Only for use in the treatment of resistant M. tuberculosis infections


    Antimicrobials that act by cell wall inhibition3

    Antimicrobials that act by cell-wall inhibition

    • Cell-wall synthesis is organized by;

      • Transpeptidase,

      • Carboxypeptidase,

      • Endopeptidase,

        • These enzymes can also bind beta-lactam antibiotics, so;

          • also called PBPs (penicillin-binding proteins)

      • In a bacterium that grows;

        • Antibiotics are bound to PBPs

        • Otolytic enyzmes are released

        • Cell-wall cannot be produced


    Antimicrobials that act by cell wall inhibition4

    Antimicrobials that act by cell-wall inhibition

    • Numerous PBPs can be found in a bacterium

    • These enzymes are classified as PBP-1, PBP-2, PBP-3, etc., respectively, based on the order of their molecular weights

    • If a PBP with a mid-range weight is discovered later on, it is named as PBP-1a, PBP-1b, etc.


    Antimicrobials that act by cell wall inhibition5

    Antimicrobials that act by cell-wall inhibition

    • Affinity to PBPs differs among beta-lactam antibiotics

    • Therefore, efficacy of distinct beta-lactam antibiotics on distinct bacteria are different

    • Most significant effect of beta-lactams are on transpeptidases

    • Usually, beta-lactams with an affinity to larger PBP molecules are more potent


    Antimicrobials that act by inhibition of protein synthesis

    Antimicrobials that act by inhibition of protein synthesis

    • Aminoglycosides (30S);

      • streptomycin, kanamycin, gentamicin, tobramycin, amikacin

  • Tetracyclines (30S);

    • tetracycline, doxycycline, minocycline

  • Macrolides (50S);

    • erythromycin, azithromycin, clarithromycin, spiramycin, roxithromycin

  • Ketolides (50S);

    • telithromycin

  • Lincosamide (50S);

    • clindamycin, lincomycin

  • Chloramphenicol (50S)

  • Streptogramins (50S);

    • quinupristin-dalfopristin

  • Oxazolidinone (50S);

    • linezolid

  • Fusidic acid


  • Aminoglycosides

    Aminoglycosides

    • By binding to bacterial ribosomes;

      • inhibition of protein synthesis

      • mismatch reads in mRNA codons; incorporation of wrong aa’s in polypeptides; non-functional proteins

      • mis-reading as a stop codon; termination before a completed synthesis of a protein


    Aminoglycosides1

    Aminoglycosides

    • They pass bacterial membrane in two steps

      • In the first step, energy is not required

      • In the second step, energy is required

    • Their effect is bactericidal

      • Inhibiton of protein synthesis, and

      • Disruption of cytoplasmic membrane structure


    Aminoglycosides2

    Aminoglycosides

    • Active transport with energy and oxygen is inhibited by;

      • cations like Ca ve Mg,

      • in anaerobic conditions,

      • in low pH,

      • in high osmolarity,

    • Therefore, activity is decreased;

      • in anaerobic conditions of abcesses, or

      • acidic and hyperosmolar environment of urine


    Tetracyclines

    Tetracyclines

    • in Gr (-) bacteria, they can enter through the porin chanells in cell-wall by passive diffusion

    • bind reversibly to the 30S ribosomal subunits, thus block the binding of aminoacyl-transfer RNA (tRNA) to the 30S ribosome-mRNA complex

      • peptide chain is not elongated

    • Bacteriostatic

    • However, aluminum, calcium, magnesium, iron in the nutritional uptake,

      • causes chelation with and inactivates tetracycline


    Chloramphenicol

    Chloramphenicol

    • by binding reversibly to the peptidyl transferase component of the 50S ribosomal subunit, blocks peptide elongation

    • Bacteriostatic


    Macrolides

    Macrolides

    • by their reversible binding to the 23S rRNA of the 50S ribosomal subunit, which blocks polypeptide elongation (through blocking tRNA molecule)

    • Bacteriostatic


    Antimicrobial agents mechanisms of action and resistance

    Lincosamides, Streptogramins:

    • blocks protein elongation by binding to the 50S ribosome (same site withmacrolides)

      Mupirocin:

    • inhibitsisoleucine t-RNA synthetasethatintegratesisoleucinandtRNA

      • inhibitsbacterialtRNAsynthesis, and

      • protein synthesis

        Fucidicacid:

    • acts as a bacterial protein synthesis inhibitor by preventing the turnover of elongation factor G (EF-G) from the ribosome


    Antimicrobials that act by inhibition of nucleic acid synthesis

    Antimicrobials that act by inhibition of nucleic acid synthesis

    • Quinolones

      • nalidixic acid

      • fluoroquinolones

        • ciprofloxacin, levofloxacin, ofloxacin, norfloxacin, pefloxacin, levofloxacin, moxifloxacin

    • Rifampin

    • Metronidazole


    Quinolones

    Quinolones

    • Mechanism of effect;

      • inhibits the enzymes (topoisomerase type II (gyrase) or topoisomerase type IV) that have functions in;

        • DNA replication

        • DNA recombination

        • DNA repair

      • Therefore, inhibits nucleic acid synthesis

      • The DNA gyrase-A subunit is the primary quinolone target in gram-negative bacteria, whereas topoisomerase type IV is the primary target in gram-positive bacteria


    Quinolones1

    Quinolones

    • Bactericidal

    • There may be other mechanisms effective

    • The differences in efficacy of distinct quinolones caused by differences in binding to enyzme-DNA complexes


    Rifampicin rifampin

    Rifampicin (Rifampin)

    • binds to DNA-dependent RNA polymerase and inhibits the initiation of RNA synthesis

    • Bactericidal

    • Similar enzymes in mammalian cells are less sensitive to rifampicins


    Antimetabolites

    Antimetabolites

    • Sulfonamides

    • Trimethoprim

    • Dapsone (sulfons)


    Antimicrobials that act by an i ncrease in cell membrane permeability

    Antimicrobials that act by an increase in cell-membrane permeability

    • Polymyxins and Colistin

      • act like cationic detergents and damagecytoplasmic membrane by interacting with the phospholipids and incresing the permeability

      • also damage the cell-wall lipopolisaccarides in Gr (-) bacteria


    Mechanisms of action

    Mechanisms of action


    Mechanisms of action1

    Mechanisms of action


    Mechanisms of action2

    Mechanisms of action


    Antimicrobial consumption

    Antimicrobial consumption


    Antimicrobial spectrum

    Antimicrobial spectrum

    • Range of activity of an antimicrobialagainstbacteria

    • Broadspectrum: inhibits a widevariety of gram-positiveand gram-negativebacteria

    • Narrowspectrum: activeagainst a limitedvariety of bacteria


    Antimicrobial spectrum1

    Antimicrobial spectrum


    Penicillins

    Penicillins


    Cephalosporins and cephamycins

    Cephalosporins and Cephamycins


    Other beta lactams

    Other beta-lactams


    Resistance to beta lactams

    Resistance to beta-lactams

    • Three general mechanisms:

      • (1) prevention of the interaction between the antibiotic and the target PBP,

      • (2) modification of the binding of the antibiotic to the PBP, and

      • (3) hydrolysis of the antibiotic by β-lactamases.

    • (1) seen only in gram-negative bacteria (particularly Pseudomonas species), because they have an outer membrane that overlies the peptidoglycan layer.

      • Penetration of β-lactam antibiotics into gram-negative rods requires transit through pores in the outer membrane.

      • Changes in the proteins (porins) that form the walls of the pores can alter the size or charge of these channels and result in the exclusion of the antibiotic.

    • (2) modification of the β-lactam antibiotic binding to the PBP.

      • (a) an overproduction of PBP (a rare occurrence),

      • (b) acquisition of a new PBP (e.g., methicillin resistance in Staphylococcus aureus), or

      • (c) modification of an existing PBP through recombination (e.g., penicillin resistance in Streptococcus pneumoniae) or a point mutation (penicillin resistance in Enterococcus faecium).


    Resistance to beta lactams1

    Resistance to beta-lactams

    • Three general mechanisms:

      • (1) prevention of the interaction between the antibiotic and the target PBP,

      • (2) modification of the binding of the antibiotic to the PBP, and

      • (3) hydrolysis of the antibiotic by β-lactamases.

    • (3) Finally, bacteria can produce β-lactamases that inactivate the β-lactam antibiotics.

      • More than 200 different β-lactamases have been described.

      • Some are specific for penicillins (i.e., penicillinases), cephalosporins (i.e., cephalosporinases), or carbapenems (i.e., carbapenemases), whereas others have a broad range of activity, including some that are capable of inactivating most β-lactam antibiotics.

      • Unfortunately, simple point mutations in the genes encoding these enzymes have created β-lactamases with activity against all penicillins and cephalosporins.

        • These β-lactamases are referred to as extended-spectrum β-lactamases (ESBLs) and are particularly troublesome because they are encoded on plasmids that can be transferred from organism to organism.


    Resistance to vancomycin

    Resistance to Vancomycin

    • Some organisms are intrinsically resistant to vancomycin:

      • Leuconostoc, Lactobacillus, Pediococcus, and Erysipelothrix

      • some species of enterococci; Enterococcus gallinarum, Enterococcus casseliflavus

    • Some species of enterococci (particularly Enterococcus faecium and Enterococcus faecalis) have acquired resistance to vancomycin.

      • resistance genes, primarily vanA and vanB, can be carried on plasmids

    • More importantly, the gene for vancomycin resistance can be transferred to S. aureus in laboratory.

      • a transposon on a multiresistance conjugative plasmid has been transferred in vivo from E. faecalis to a multiresistant S. aureus.

      • The transposon then moved from the E. faecalis plasmid and recombined and integrated into the S. aureus multiresistance plasmid.


    Resistance to isoniazid ethionamide ethambutol and cycloserine

    Resistance to Isoniazid, Ethionamide, Ethambutol, and Cycloserine

    • Resistance to these four antibiotics results primarily from reduced drug uptake into the bacterial cell or alteration of the target sites.


    Resistance to aminoglycosides

    Resistance to Aminoglycosides

    • Resistance to the antibacterial action of aminoglycosides can develop in one of four ways:

      • (1) mutation of the ribosomal binding site,

      • (2) decreased uptake of the antibiotic into the bacterial cell,

      • (3) increased expulsion of the antibiotic from the cell, or

      • (4) enzymatic modification of the antibiotic.

    • The most common mechanism of resistance is enzymatic modification of aminoglycosides.

    • This is accomplished by the action of phosphotransferases (APHs; seven described), adenyltransferases (ANTs; four described), and acetyltransferases (AACs; four described) on the amino and hydroxyl groups of the antibiotic.

    • The other mechanisms by which bacteria develop resistance to aminoglycosides are relatively uncommon.


    Resistance to tetracyclines

    Resistance to Tetracyclines

    • Resistance to the tetracyclines mey be due to;

      • decreased penetration of the antibiotic into the bacterial cell,

      • active efflux of the antibiotic out of the cell,

      • alteration of the ribosomal target site, or

      • enzymatic modification of the antibiotic.

    • Mutations in the chromosomal gene encoding the outer membrane porin protein, OmpF, can lead to low-level resistance to the tetracyclines, as well as to other antibiotics (e.g., β-lactams, quinolones, chloramphenicol).

    • Researchers have identified a variety of genes that control the active efflux of the tetracyclines from the cell in different bacteria. This is the most common cause of resistance.


    Resistance to macrolides

    Resistance to Macrolides

    • Resistance to macrolides most commonly stems from the methylation of the 23S ribosomal RNA, preventing binding by the antibiotic.

    • Other mechanisms of resistance include inactivation of the macrolides by enzymes (e.g., esterases, phosphorylases, glycosidase) or mutations in the 23S rRNA and ribosomal proteins.


    Resistance to quinolones

    Resistance to Quinolones

    • Resistance to the quinolones is mediated by chromosomal mutations in the structural genes for DNA gyrase and topoisomerase type IV.

    • Other mechanisms include overexpression of efflux pumps that actively eliminate the drug and decreased drug uptake caused by mutations in the membrane permeability regulatory genes.

    • Each of these mechanisms is primarily chromosomally mediated.


    Antibiotic combinations

    Antibiotic combinations

    To broaden the spectrum for empirical therapy or treatment of polymicrobial infections

    To prevent the emergence of resistant microorganisms

    To achieve a synergistic killing effect


    Antibiotic combinations1

    Antibiotic combinations

    A good example is the treatment of tuberculosis


    A synergism b antagonism

    A)Synergism B)Antagonism


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