Introduction to antimicrobial agents

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1 Introduction to antimicrobial agents Kwan Soo Ko

2 Action mechanisms of antimicrobials Bacteriostatic agents, such as tetracycline - Inhibit the growth and multiplication of bacteria - Upon exposure to a bacteriostatic agent, cell in a susceptible population stop dividing - If the agent removed, the cells once again multiply Bactericidal agents, such as fluoroquinolones - Not only inhibit the growth, but also trigger pathways within the cell that lead to cell death - The actions of bactericidal agents are irreversible so once susceptible cells exposed to a bactericidal agent, they die

3 Action mechanisms of antimicrobials Inhibition of cell wall synthesis Inhibition of protein synthesis Inhibition of nucleic acid synthesis (DNA or RNA) Antimetabolites

4 Inhibition of Cell Wall Synthesis The most common mechanism β-lactam antibiotics - penicillins, cephalosporins, cephamycins, carbapenems, monobactams, β-lactamase inhibitors Vancomycin, daptomycin, bacitracin, and antimycobacterial agents

5 Inhibition of Protein Synthesis The second largest class of antibiotics Aminoglycosides Tetracyclines Glycylcyclines Oxazolidinones Chlroamphenicol Macrolides Ketolides Clindamycin Streptogramins

6 Inhibition of Nucleic Acid Synthesis Inhibition of DNA synthesis - (Fluoro)quinolones Inhibition of RNA synthesis - Rifampin

7 Antimetabolites Sulfoamides & Trimethoprim - For many organisms, para-aminobenzoid acid (PABA) is an essential metabolite in the synthesis of folic acid, an important precursor to the synthesis of nucleic acids - Sulfonamides - Trimethoprim (TMP)

8 Penicillins & β-lactam Inhibitors Kwan Soo Ko

9 Penicillins By Alexander Fleming in The Nobel Prize in Physiology or Medicine "for the discovery of penicillin and its curative effect in various infectious diseases" Sir Alexander Fleming Ernst Boris Chain Sir Howard Walter Florey

10 Chemistry of penicillins β-lactam ring, essential for antibacterial activity Side chain for antibacterial spectrum and pharmacologic properties of a particular penicillin

11 Chemistry of penicillins Emergence of β-lactamase-producing organisms prompts development of compounds resistant to hydrolysis by β-lactamases Isolation of penicillin nucleus, 6-amino-penicillanic acid, from Penicillium chrysogenum production and testing of numerous semisynthetic penicillins methicillin against β-lactamase-producing S. aureus ampicillin against selected gram-negative bacilli carbenicillin against P. aeruginosa

12 S. aureus P. aeruginosa

13 Action mechanism of penicillins Inhibition of cell wall synthesis - Simply by blocking cell wall synthesis? overly simplistic! Synthesis of cell wall in bacteria - in a series of enzymatic steps involving at least 30 enzymes

14 Disaccharide monomer of N-acetylglucosamine (NAG) and N-acetylmuramic (NAM) pentapeptide Cytoplasmic reactions generating cell wall precursors & Transglycoslase reaction linking the subunit to peptidoglycan polymer not sensitive to penicillin

15 Action mechanism of penicillins Penicillin inhibits enzymes that catalyze the final step in bacterial cell wall assembly (formation of cross-links bridging peptidoglycan, giving structural integrity) Pentapeptide with amino acid residues alternating between L- and D-stereoisomers, terminating in D- alanyl-d-alanine

16 Action mechanism of penicillins Transpeptidation - formation of a amide bond between the terminal-free amine group of a stem peptide - penultimation of D-alanine of a pentapeptide, displacing the terminal D-alanine in the process - sensitive to inhibition by penicillin

17 Penicillin-binding proteins (PBPs) - Catalyze penicillin-sensitive reactions - Bifunctional enzymes (transpeptidase & transglycosylase) - Be inhibited by β-lactams through covalent binding of the active site serine residue - Binding to and inhibition of PBPs mediate the antibacterial activity of β-lactam antibiotics

18 Action mechanism of penicillins - β-lactams produce lethal effect on bacteria by inactivation of multiple PBPs, but inhibition of cell wall synthesis by itself is not necessarily lethal (nongrowing cells & osmotically protected cells) - Lethal effect in both gram-positive and gram-negative bacteria is probably cell-dependent - Inhibition of PBPs leads to disruption of a crucial event probably at the time of cell division - Disturbed morphogenesis is hypothesized to initiate cell death

19 Classification Conveniently, 5 classes on the basis of antibacterial activity (1)Natural penicillins, penicillin G & penicillin (2)Penicillinase-resistant penicillins, methicillin, nafcillin & isoxazolyl penicillins (3)Aminopenicillins, ampicillin & amoxicillin (4)Carboxypenicillins, carbenicillin & ticarcillin (5)Acyl ureidopenicillins, azlocillin, mezlocillin & piperacillin Carboxypenicillins & acyl ureidopenicillin - referred as antipeudomonal penicillins

20 Susceptibilities of penicillins Natural penicillins - most active against non-β-lactamase-producing grampositive bacteria, anaerobes, and selected gram-negative cocci (such as Neisseria) Semisynthetic penicillinase-resistant penicillins - only for penicillin-resistant S. aureus & S. epidermidis Aminopenicillins - same spectrum as penicillin G - active against non-β-lactamase-producing gram-negative cocci & Enterobacteriaceae

21 Susceptibilities of penicillins Carboxypenicillins & ureidopenicillins - active against ampicillin-resistant gram-negative aerobic rods, such as P. aeruginosa - Carboxypenicillins are less active against streptococci and Haemophilus spp. - Ureidopenicillins are more active against gram-negative bacteria other than Pseudomonas

22 β-lactamse inhibitors Clavulanic acid and penicillanic acid sulfone derivaties (themselves β-lactam compounds) Weak antibacterial activity - hydrolysis of β-lactam-carbonyl bond of β-lactams When combined with a β-lactam (substrate for class A β- lactamases), inhibitor prevent hydrolysis of antibiotic and thereby restoring its activity Three β-lactamase inhibitors in clinical use - Clavulanic acid, sulbactam & tazobactam - Each inhibitor is available only as a fixed-combination preparation - Effective only against Ambler class A β-lactamases

23 Clavulanic acid - Naturally occurring, weak antimicrobial agent (Streptomyces clavuligerus) -Inhibits β-lactamases from staphylococci and many gram-negative bacteria - Suicide inhibitor by forming an irreversible acyl enzyme complex with β-lactamase - Synergistic with various penicillins and cephalosporins

24 Sulbactam - Semisynthetic 6-desaminopenicillin sulfone with weak antibacterial activity - Effective inhibitor of certam plasmid-mediated and chromosomally mediated β-lactamases - Alone active against Neisseria gonorrhoeae, N. meningitis, and some Acinetobacter spp. - Synergically active with penicillins and cephalosporins

25 Tazobactam - Penicillanic acid sulfone derivative structurally related to sulbactam -Suicidal β-lactamase inhibitor - Binds to bacterial PBP1 or PBP2 - Available as a 1:8 ratio dosage combination with piperacillin

26 Resistance to penicillins Four mechanisms - Destruction of antibiotic by β-lactamase - Failure of antibiotic to penetrate the outer membrane of gram-negative bacteria to reach PBP targets - Efflux of drug across the outer membrane of gram-negative bacteria - Low-affinity binding of antibiotic to target PBPs

27 β-lactamase The most common in gram-negative bacteria - Covalently react with the β-lactam ring, rapidly hydrolyze, and destroy activity of the drug - Be categorized into four classes Ambler class A through D based on amino acid sequence similarity and molecular structure

28 β-lactamase Molecular Class Major Subtypes Preferred Substrates Inhibitor Gram-positive β-lactamase 2a Penicillins Clavulanate Gram-negative β-lactamase (e.g., TEM-1 and SHV-1) 2b Penicillins, some cephalosporins Clavulanate Main Genetic Localization Chromosomal or plasmid, inducible Plasmid or chromosomal A ESBL2be Inhibitor-resistant TEM β-lactamase 2br Carbenicillin-hydrolyzing β-lactamase 2c Cephalosporin hydrolyzing β-lactamase 2e Carbapenem hydrolyzing β-lactamase 2f Penicillins, narrow-spectrum and third-generation cephalosporins, monobactams Clavulanate Plasmid Penicillins Clavulanate? Plasmid Penicillins, carbenicillin Clavulanate? Plasmid Cephalosporins Clavulanate Chromosome, inducible Penicillins, cephalosporins, carbapenems B Metallo-β-lactamase 3 All β-lactams except monobactam C AmpC-type cephalosporinase 1 Cephalosporins, penicillins D Cloxacillin-hydrolyzing β-lactamase 2d Clavulanate EDTA, divalent cation chelators Cloxacillin, monobactams Chromosomal Chromosomal Penicillins, cloxacillin Clavulanate? Plasmid Chromosomal (inducible); constitutive, plasmidencoded enzymes increasingly reported

29 β-lactamase Class A, C & D - contain penicillin-binding motifs: PBPs - differ from other PBPs in that they typically are smaller in size and they are not cell wall synthetic enzymes - acylation of the active site serine and hydrolysis of the acyl intermediate in a deacylation reaction regenerating the active enzyme - deacylation rate of β-lactamase usually is greatly faster, rapidly hydrolyzing and turning over β-lactam molecules Class B - structuraly unrelated to PBPs -Zn 2+ -dependent enzymes: use different series of reactions to open the β-lactam ring

30 Class A β-lactamase Penicillinase (some, cephalosporinase or carbapenemase) Be inhibited by β-lactamase inhibitors such as clavulanic acid Point mutations resistance or extension of spectrum of activity including 3rd-generation cephalosporins and monobactams (extended-spectrum β-lactamases, ESBLs)

31 Other β-lactamase Class C β-lactamase - Cephalosporinases not inhibited by clavulanic acid - usually be encoded on the chromosome and inducible Class B β-lactamase - broad-spectrum enzymes - be inhibited by chelating agents - can hydrolyze all β-lactams except monobactams

32 Loss of porin in outer membrane Outer membrane of gram-negative bacteria - important barrier to drug penetration and important component of resistance β-lactamases of gram-negative bacteria - located in periplasmic space between inner cytoplasmic membrane and outer lipopolysaccharide membrane β-lactams can transverse porin channels to the periplasmic space and bind to target PBPs - Absence or deletion of a critical porin can result in resistance

33 Efflux Drug that enters the periplasmic space is pumped back across the outer membrane Independent to other mechanisms - but co-operation with exclusion of antibiotic by porins and destruction of antibiotic by β-lactamases Species difference in porins, pumps, β-lactamases, and target PBPs determined whether the organism is susceptible or resistant to a particular antibiotic

34 Production of PBP with low affinity Result of mutations in PBP genes - as in penicillin-resistant S. pneumoniae or Neisseria spp. Due to the presence of extra, low-affinity PBP - PBP5 by E. faecium or PBP2a by MRSA PBP2a - structural changes result in energetically unfavorable interactions between antibiotic and protein active site is inactivated not at all or too slowly to effectively block cell wall synthesis and bacterial growth

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