Antibiotics Production and Mechanisms
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Questions and Answers

What compound is produced from the addition of corn steep liquor in the fermentation process?

  • Penicillin F
  • Penicillin G (correct)
  • Mono-substituted acetic acid
  • Phenylacetic acid

    • Which of the following statements accurately describes the incorporation of acids during penicillin production?

  • Only mono-substituted acetic acids are utilized. (correct)
  • Acetic acids are not necessary for penicillin production.
  • No acidic compounds are incorporated.
  • Poly-substituted acetic acids are primarily used.

    • What is the structure labeled as the β-lactam ring associated with?

  • Penicillin G only
  • Thiazolidine ring
  • Only mono-substituted penicillins
  • All penicillins (correct)

    • What type of enzyme is penicillin acylase, and where is it derived from?

    <p>Acylase from E. coli</p> Signup and view all the answers

    What happens in the absence of substituted acetic acid in the fermentation medium?

    <p>The mold cannot produce any penicillins.</p> Signup and view all the answers

    What is the mechanism by which vancomycin exerts its antibacterial effect?

    <p>Preventing crosslink formation of bacterial cell wall components.</p> Signup and view all the answers

    What is the primary reason for vancomycin resistance in some Enterococci?

    <p>Alteration in the ligase activity producing D-Ala-D-Lactate.</p> Signup and view all the answers

    Which of the following antibiotics is known as the only available oral treatment for MRSA infections?

    <p>Linezolid</p> Signup and view all the answers

    What effect does the D-Ala-D-Lactate sequence have on vancomycin's efficacy?

    <p>It results in a 1000-fold reduction in affinity for vancomycin.</p> Signup and view all the answers

    How do altered ligases contribute to the resistance against vancomycin?

    <p>They allow for the synthesis of D-Ala-D-Lactate, reducing vancomycin's effectiveness.</p> Signup and view all the answers

    What is a primary reason for the reduced profitability of antibacterials compared to drugs for chronic conditions?

    <p>Antibacterials are generally used for acute conditions.</p> Signup and view all the answers

    Which of the following antibiotics is produced by the fungus Penicillium chrysogenum?

    <p>Griseofulvin</p> Signup and view all the answers

    Which type of antibacterial agent inhibits cell growth?

    <p>Bacteriostatic</p> Signup and view all the answers

    What characteristic is NOT true for bacterial cells compared to eukaryotic cells?

    <p>Bacterial cells have defined nuclei.</p> Signup and view all the answers

    Which of the following is an example of a Gram-negative bacterium?

    <p>Escherichia coli</p> Signup and view all the answers

    Why are newly approved antibacterials typically not used as first-line treatments?

    <p>They are reserved until older classes are ineffective.</p> Signup and view all the answers

    Which class of antibiotics does NOT interfere with bacterial cell wall synthesis?

    <p>Macrolides</p> Signup and view all the answers

    What is one of the key differences between prokaryotic and eukaryotic cells?

    <p>Prokaryotic cells have cell walls.</p> Signup and view all the answers

    What is the role of calcium ions in the activity of daptomycin?

    <p>They enhance the bactericidal activity by facilitating membrane interaction.</p> Signup and view all the answers

    What feature characterizes daptomycin's chemical structure?

    <p>A depsipeptide ring formed by amino acids with some attached through a threonine residue.</p> Signup and view all the answers

    Which mechanism explains how daptomycin leads to cell death in bacteria?

    <p>It forms large pores in the membrane causing potassium efflux.</p> Signup and view all the answers

    Which of the following describes the primary cause of daptomycin resistance in certain strains of S. aureus?

    <p>Thickened cell walls preventing diffusion into the membrane.</p> Signup and view all the answers

    How does daptomycin interact with the cytoplasmic membrane?

    <p>It alters permeability leading to leakage of cellular contents.</p> Signup and view all the answers

    What can lead to daptomycin resistance associated with vancomycin-unresponsive strains?

    <p>Introduction of additional peptidoglycan layers.</p> Signup and view all the answers

    What is a significant effect of daptomycin oligomerisation when it binds to calcium?

    <p>It creates large pores in the membrane, promoting cell death.</p> Signup and view all the answers

    Which of the following conditions affects the susceptibility of bacteria to daptomycin?

    <p>Alterations in membrane lipid composition due to specific genes.</p> Signup and view all the answers

    What is the primary mechanism of resistance to chloramphenicol mediated by chloramphenicol acetyltransferases (CAT)?

    <p>They acetylate chloramphenicol so that it no longer binds to the PTC A site.</p> Signup and view all the answers

    Which of the following statements is true regarding the susceptibility of Cm-resistant strains to florfenicol?

    <p>Florfenicol can be used to treat infections caused by Cm-resistant strains due to the lack of acetylation.</p> Signup and view all the answers

    What characterizes chloramphenicol in terms of its antibacterial properties?

    <p>It is highly lipophilic and can penetrate most tissues.</p> Signup and view all the answers

    Which side effect is a significant concern when administering chloramphenicol?

    <p>Aplastic anaemia due to bone marrow suppression.</p> Signup and view all the answers

    In which clinical scenario is chloramphenicol particularly used?

    <p>For meningitis in patients with β-lactam allergies.</p> Signup and view all the answers

    What is the historical significance of streptomycin within the context of antibiotic treatment?

    <p>It was first used to treat tuberculosis in 1944.</p> Signup and view all the answers

    What role do CAT genes play in antibiotic resistance?

    <p>They can be found on both plasmids and chromosomes.</p> Signup and view all the answers

    What is a unique structural aspect of florfenicol compared to chloramphenicol?

    <p>It lacks the 3-hydroxy group, preventing acetylation.</p> Signup and view all the answers

    What role do variations in R′ play in sulphonamides?

    <p>They are responsible for the different sulphonamides used clinically.</p> Signup and view all the answers

    What is the consequence of sulphonamides being incorporated into macromolecules?

    <p>They inhibit further synthesis of folic acid.</p> Signup and view all the answers

    What is the function of dihydropteroate synthetase in folic acid synthesis?

    <p>It binds PABA and initiates the synthesis process.</p> Signup and view all the answers

    What can reverse the incorporation of sulphonamide into macromolecules?

    <p>The introduction of additional PABA.</p> Signup and view all the answers

    What is a property of sulphapyridine that makes it effective against pneumonia?

    <p>Increased activity compared to other sulphonamides.</p> Signup and view all the answers

    What characteristic of sulphathiazole poses a risk in terms of side effects?

    <p>Poor ionization leading to potential kidney blockages.</p> Signup and view all the answers

    Which of the following is a similarity between sulphanilamide and PABA?

    <p>They share similar molecular dimensions and properties.</p> Signup and view all the answers

    How does the electron-withdrawing nature of pyrimidine affect sulphadiazine?

    <p>It decreases the pKa and increases ionization.</p> Signup and view all the answers

    The inactivity of prodrugs is due to what factor related to their structure?

    <p>Variation in substituents at specific positions.</p> Signup and view all the answers

    The initial step in folic acid synthesis requires which of the following?

    <p>The presence of pyrophosphokinase (PPPK).</p> Signup and view all the answers

    What is the significance of H-bonding in the process described?

    <p>It enhances the binding of sulphonamides to enzymes.</p> Signup and view all the answers

    Which of the following statements is true regarding the hydrolysis of inactive prodrugs?

    <p>It releases the active amino group within the body.</p> Signup and view all the answers

    What happens when excess PABA is present in the reaction?

    <p>Folic acid formation can resume.</p> Signup and view all the answers

    What type of bond plays a critical role in the interaction of sulphonamides with enzymes?

    <p>Hydrogen bonds and ionic bonds.</p> Signup and view all the answers

    Study Notes

    • This material has been copied and communicated to you by the University of Sydney pursuant to Part VB of the Copyright Act 1968 (The Act).
    • Material in this communication may be subject to copyright under The Act.
    • Any further copying or communication of this material by you may be subject to copyright protection under The Act.
    • Do not remove this notice.

    Acknowledgement of Country

    • We acknowledge the traditional owners of the land on which we meet.
    • We pay our respects to their Elders, past, present and emerging.
    • We acknowledge their ongoing cultures and connections to the lands and waters of NSW.

    PHAR2921 Antimicrobials

    • Course name: Antimicrobials
    • Course code: PHAR2921
    • Lecturer: Paul Groundwater
    • Email: [email protected]
    • Textbook: Antibacterial Agents by Rosaleen J. Anderson, Paul W. Groundwater, Adam Todd and Alan J. Worsley. Published by Wiley

    Australian Pharmacy Council (APC) Curriculum Learning Domains

    • Learning Domain 1: The Health Care Consumer
      • Pharmacist expertise ensures optimal health outcomes and minimizes harm.
      • Promotes good health and disease prevention.
      • Includes disease management, care planning, clinical guidelines, and prescribing guidelines.
    • Learning Domain 2: Medicines: Drug Action
      • Covers molecular, cellular, biological, and physical aspects of drug action.
      • Includes clinical uses, contraindications, adverse reactions, and drug interactions.
      • Discusses drug absorption, distribution, metabolism, excretion, and influences on these factors, including formulation, administration, dosage regimens, and the impact of ageing and disease.
      • Explores future therapeutic approaches.
    • Learning Domain 3: Medicines: The Drug Substance
      • Details the sources and purification of bio-technological, chemical synthetic, immunological, mineral, and plant-based substances used in medicine.

    Antibacterial Chemotherapy Learning Outcomes

    • Understand the basis of antibacterial agent selectivity.
    • Understand different sources, modes of action, and resistance of antibacterial agents from various classes.
    • Inhibition of cell wall synthesis (β-lactams):
    • Inhibition of metabolism (sulphonamides):
    • Inhibition of nucleic acid transportation and replication (quinolones):
    • Inhibition of protein synthesis (chloramphenicol, macrolides):
    • Inhibition of cell membrane function (isoniazid):
    • Understand the role of some bacterial pathogens in infectious disease.

    Summary

    • How do antibacterial agents arise? For example, is drug target specific to prokaryotic cells?
    • Understanding the mechanism of action helps to understand how resistance arises.
    • Resistance can arise via:
      • Drug modification (e.g., β-lactams, chloramphenicol, aminoglycosides, isoniazid)
      • Target modification (e.g., β-lactams, vancomycin, daptomycin, quinolones, sulphonamides, aminoglycosides, linezolid, macrolides, isoniazid, azoles)
      • Increased levels of drug target (e.g., D-cycloserine, isoniazid)
      • Decreased accumulation or increased efflux (e.g., quinolones, chloramphenicol, aminoglycosides, macrolides, azoles)

    "The World is Facing an Antibiotic Apocalypse"

    • Prof Dame Sally Davies (UK CMO)
    • Antibiotic resistance is a significant global concern with projections of substantial impact in 2050.
    • A range of health risks (e.g., tetanus, road traffic accidents) are highlighted.

    Antibacterial Drug Discovery

    • The golden age of antibacterial drug discovery has ended with the last novel clinically approved agent in 2000.
    • Reasons include:
      • Loss of research expertise in the pharmaceutical industry.
      • Profitability issues as antibacterials are often used for short-term acute conditions.
      • Inevitability of resistance reducing the drug's efficacy.
      • Newly approved antibacterials are held in reserve until older classes become ineffective.

    Antibacterial Chemotherapy

    • Antibacterial agents: can be bacteriostatic (inhibiting cell growth) or bactericidal (killing bacterial cells)
    • Antibiotics are chemical substances produced by microorganisms (e.g., penicillin from Penicillium chrysogenum).
    • First known antibiotic was against anthrax.
    • Different classes of microorganisms produce antibiotics (e.g., fungi – penicillins; bacteria – streptomycin, chloramphenicol, macrolides, tetracyclines; nocardia – rifamycins).

    Gram Positive and Gram Negative Cell Walls

    • Diagrams show the different structures of cell walls for Gram-positive bacteria, Gram-negative bacteria, and Mycobacteria, highlighting the components like lipoteichoic acid, teichoic acid, peptidoglycan, phospholipid bilayer, outer membrane, lipoproteins, lipopolysaccharides, O-antigen etc.
    • Diagrams name various bacteria types.

    The Bacterial Cell (Prokaryotic)

    • Diagram of a prokaryotic cell, pointing out components like cell wall, periplasmic space, plasma membrane, ribosomes, DNA, pili and flagellum, and specific antibiotics targeting different areas.

    Selective Toxicity to the Bacterial Cell

    • Bacterial cells have a cell wall and plasma membrane protecting them from osmotic pressure.
    • Bacterial cells lack defined nuclei and organelles like mitochondria.
    • Bacterial cell biochemistry differs significantly from eukaryotic cells.

    Inhibition of Bacterial Cell Wall Synthesis

    • These agents interfere with cell wall synthesis in growing bacteria causing weakened cell wall, lysis, and cell death.
    • Bactericidal agents affect mature cell walls by affecting the balance between penicillin-binding proteins (PBPs) and murein hydrolase in the process of cell wall synthesis and lysis.
    • Penicillins, cephalosporins, monobactams, carbapenems contain a β-lactam ring.
    • Penicillins were discovered in 1929.

    B-Lactams

    • Beta-lactams, such as piperacillin/tazobactam, amoxicillin, ceftriaxone, cefoxitin, aztreonam, and imipenem have varying uses (e.g., treatment of P. aeruginosa, pneumonia, and infections).

    Penicillins

    • Production, isolation, and the demonstration of selectivity by Chain, Florey, Abraham and Heatley.
    • Nobel prize in 1945 for Fleming, Chain and Florey.
    • Process improvements (deep fermentation) developed during World War II.
    • Chemical structures of penicillin and 6-aminopenicillanic acid presented.
    • Properties and varying comments (e.g., increased acid stability, resistance to Staphylococcal penicillinase) given for different penicillins.

    Other Beta-Lactams

    • Cephalosporins, first isolated from Cephalosporium in 1948 by Brotzu, have broad spectrum activity.
    • Latest cephalosporins have 3rd/4th generations showing increasing activity against ESBL and AmpC cephalosporinases.

    Penicillins - Acid Sensitivity and Oral Administration

    • Beta-lactam ring is sensitive to hydrolysis.
    • Sensitivity to acid can be overcome by:
      • Introduction of electron-withdrawing group on amide side-chain (e.g., penicillin V).
      • Introduction of bulky group on the amide side-chain (e.g., ampicillin/amoxicillin).

    Penicillins - Oral Administration

    • Some penicillins (e.g., ampicillin and amoxicillin) are poorly absorbed due to their zwitterionic nature.
    • Absorption may be enhanced by prodrug esters that are then converted to active penicillins after absorption.

    β-Lactamase Inhibitors (BLIs)

    • Different beta-lactamases have different substrates.
    • Beta-lactamases are present and cleave the beta-lactam ring, leading to antibiotic inactivation.
    • Examples of BLIs: clavulanic acid, co-amoxiclav, unasyn, tazocin or zosyn.

    Non β-Lactam BLIs Inhibitors

    • Examples of BLIs include avibactam, relebactam, and vaborbactam.
    • These are often used with other antibacterials.

    Antibiotic Resistance

    • Microbiological: Intrinsic resistance - natural organism resistance to antibiotic, and acquired resistance due to genetic mutation or plasmid acquisition.
    • Clinical: Failure to achieve antimicrobial concentration to inhibit organism growth.

    Penicillins Disrupt Peptidoglycan Formation

    • Prokaryotic cell walls are composed of peptidoglycan.
    • Gram-positive bacteria have a complex cell wall which includes teichoic acids.
    • Gram-negative bacteria have a thinner cell wall embedded in a lipid outer membrane.
    • β-lactams interfere with peptidoglycan formation.
    • Penicillin-binding proteins (PBPs) are essential in the final stages of peptidoglycan synthesis.

    Peptidoglycan

    • Peptidoglycan consists of parallel sugar backbones (NAG and NAM).
    • Peptide chains are attached to NAM via carboxylic acid residues.
    • Peptide chains are linked together strengthening the cell wall via crosslink formation catalyzed by peptidoglycan transpeptidase.
    • Cross-linking is inhibited by β-lactams.

    Peptidoglycan Formation

    • Diagram showing the different types involved in the process of peptidoglycan formation.

    Cycloserine

    • D-Cycloserine (DCS) is produced by Streptomyces and is used in treatment of tuberculosis.
    • DCS inhibits alanine racemase (reducing the production of D-Ala) and D-Ala-D-Ala ligase (responsible for D-Ala-D-Ala dipeptide coupling).

    Alanine Racemase (ALR)

    • Bacterial enzyme involved in racemizing L-alanine to D-alanine.
    • Mechanism involves a Schiff base with pyridoxal 5'-phosphate.

    D-Ala-D-Ala Ligase

    • Enzyme responsible for coupling D-Ala residues to form the D-Ala-D-Ala dipeptide necessary for peptidoglycan crosslink formation.

    Cycloserine

    • Orally available antibiotic.
    • Used in combination therapies for TB treatment.
    • Serious side effects including depression and convulsions.
    • Action mechanism: inhibits enzymes that synthesise GABA.
    • Resistance to treatment: due to overproduction of D-Ala racemase.

    Vancomycin (Vancocin)

    • Glycopeptide antibiotic produced by Streptomyces orientalis.
    • Usually given intravenously due to poor oral absorption and side effects.
    • Used in the treatment of Clostridioides difficile-associated disease, and for vancomycin-resistant infections.

    MRSA (Methicillin-Resistant Staphylococcus Aureus)

    • S. aureus bacteria causing various infections (e.g. skin, pneumonia, septicimia, meningitis) can cause severe toxic shock syndrome.
    • MRSA emerged in the 1990s due to plasmid-mediated β-lactamase and a chromosomal mecA gene.
    • mecA encodes for altered penicillin-binding protein (PBP-2a) which has decreased affinity for binding β-lactams.

    Vancomycin (Vancocin)

    • Vancomycin is hydrophilic and forms hydrogen bonds with terminal D-Ala-D-Ala sequence.

    Daptomycin (Lipopeptide)

    • Lipopeptide that's used in treatment of complicated skin and skin structure infections (SSSI) caused by MRSA, and S. aureus bacteraemia.
    • Not used for pneumonia treatment due to binding with pulmonary surfactant.
    • Originally isolated from Streptomyces roseosporus.
    • Mode of action involves calcium ions and insertion into the bacterial cell membrane leading to potassium efflux which leads to fatal cell death.

    Resistance to Daptomycin

    • Resistance arises via point mutations in the mprF and yycG genes.
    • The changes to these genes influence the nature of phospholipids and can lead to changes in cell permeability.

    Quinolone Antibacterials

    • Nalidixic acid, discovered in 1962, and other first generation quinolones exhibit weak antibiotic activity and used for urinary tract infections.
    • All quinolones are readily absorbed orally and possess long half lives due to high serum protein binding.
    • Side effects: GI disturbance, rashes, prolonged QT interval, fatigue, dizziness, visual disturbances, convulsions (particularly with concurrent NSAIDs), spontaneous tendon ruptures.
    • Later generations (2nd, 3rd and 4th) have a broader spectrum, mainly due to the introduction of fluorine at the 6 position.

    Mechanisms of Quinolone Antibacterials

    • Quinolones target bacterial DNA gyrase and topoisomerase IV and inhibit bacterial replication.

    Quinolone Antibacterials

    • Mammalian cells lack DNA gyrase and topoisomerase IV, so the quinolones have some selectivity.
    • Resistance mechanisms include enzymatic alterations or efflux, mutations, and resistance-determining regions of the gyrase.

    Resistance to Quinolone Antibacterials

    • Reduced uptake and increased efflux mechanisms of quinolone antibacterials.
    • Many specific bacterial species have low membrane permeability to small hydrophobic molecules so intrinsic resistance to quinolones. E.coli has three main porins.

    Bacillus anthracis

    • Gram-positive spore-forming rod-shaped bacterium responsible for anthrax.
    • Found in soil and grazing areas.
    • Used as a biological weapon.

    Agents Which Act on Bacterial Metabolic Processes

    • Drugs that target specific bacterial metabolic processes have selective antibacterial activity.
    • Bacteria synthesize vitamins (e.g., folic acid) that can be targeted.
    • Sulphonamides are antifolates (interfere with folic acid biosynthesis).

    Sulphonamide Antibacterials

    • Prontosil, discovered in 1932 as a red dye, was the first specific synthetic antibacterial.
    • Gerhard Domagk (1939).
    • Discovered the antibacterial effect of sulphonamides (via Prontosil).
    • Sulphonamids inhibit folic acid biosynthesis.

    Sulphonamide Antibacterials

    • Sulphonamides are bacteriostatic and antifolates, interfering with bacterial folate uptake.
    • Folic acid is required by bacteria for growth but not by mammals.
    • Structure of sulphonamide and the para-aminobenzoic acid (PABA) are presented.
    • Crucial amino groups at para position in the sulphonamide group, and variations in the R group determine the effectiveness of the drugs.

    Folic Acid Synthesis

    • Diagram of folic acid synthesis pathway is presented.

    Prevention of Folic Acid Synthesis

    • Sulphonamides have similar molecular dimensions and properties to PABA.
    • These structural similarities mean they can bind to the PABA binding domain on dihydropteroate synthetase.
    • Blocking this action, preventing the formation of folic acid inhibits bacterial growth.

    Sulphonamides

    • Used in pneumonia treatments. Multiple types (e.g., sulphapyridine, sulphathiazole, sulphadiazine, sulphamethoxypyridazine, sulphamethoxazole).
    • Higher therapeutic index, but poorly soluble.
    • Variations in side-chains and heterocyclic substituents may be linked to activity variations.

    Bacterial Resistance to Sulphonamides

    • Resistance to sulphonamides can arise due to mutations in the dihydropteroate synthetase (folP) gene.
    • In Gram-negative bacteria, this resistance is often plasmid-borne.

    Trimethoprim

    • Trimethoprim (an antifolate) is a dihydrofolate reductase (DHFR) inhibitor.
    • Used in combination with sulphamethoxazole (Co-trimoxazole).
    • The combination uses sequential blocking on two enzymes involved in identical biosynthetic sequences.
    • Reduced doses of both drugs in combination result in improved patient compliance compared to when the drugs are administered separately.

    Co-trimoxazole

    • Diagram showing the sequential blocking effect of the two drugs in the same biosynthetic sequence.

    Agents Which Target Protein Synthesis

    • Chloramphenicol, tetracyclines, and erythromycin target bacterial ribosomes and inhibit protein synthesis.
    • These antibacterial agents are selective because they target components specific to bacterial ribosomes.

    Transcription and Translation

    • Overview of the processes of transcription (DNA to mRNA) and translation (mRNA to protein) within prokaryotic cells.
    • Diagrams illustrating these steps and components.

    Chloramphenicol (Chloromycetin, Cm)

    • Bacteriostatic with a broad spectrum of activity.
    • Highly lipophilic, crossing the blood-brain barrier.
    • Used in meningitis treatment for patients with beta-lactam allergies.
    • Potential side effects include aplastic anaemia, which typically occurs weeks after treatment.

    Aminoglycosides

    • Streptomycin, isolated from Streptomyces griseus, first used in treating tuberculosis.
    • Bactericidal in a concentration-dependent manner.
    • Used to treat Gram-positive, Gram-negative, and mycobacterial infections.
    • Gentamicin is often the antibiotic of choice for nosocomial Gram-negative infections.

    Concentration-versus Time-Dependent Antibacterial Activity

    • Time-dependent antibacterial activity, such as with beta-lactams, requires continuous drug concentration above the minimum inhibitory concentration (MIC) to effectively inhibit bacterial growth.
    • Concentration-dependent antibacterial agents require high concentrations to be effective and exhibit a post-antibiotic effect (PAE).

    Aminoglycoside Mechanism of Action

    • Aminoglycosides bind to the 30S ribosomal subunit, influencing mRNA decoding and causing the incorporation of incorrect amino acids.
    • This mechanism can also result in a misreading of mRNA.

    Aminoglycosides (PDB 1LC4)

    • Structural diagram illustrates aminoglycoside action on the 30S ribosomal subunit.

    Aminoglycoside Selectivity and Resistance

    • High ionization makes aminoglycosides unable to permeate mammalian cell membranes, offering selectivity.
    • Resistance can be due to impaired uptake, increased efflux, ribosomal mutations, and enzymatic modification (e.g., amino-glycoside N-acetyltransferases).

    Linezolid (Oxazolidinones)

    • FDA-approved in 2000.
    • Active against Gram-positive bacteria (e.g. vancomycin-resistant E. faecium).
    • Used to treat VRE infections, pneumonia (both CAP and nosocomial), and complicated skin and skin structure infections (CSSSI).
    • Reserve antimicrobial agent effective for MRSA treatments.
    • Inhibits protein synthesis by binding to the 50S ribosomal subunit and prevents binding of amino acid carrying tRNAs.

    Linezolid Resistance

    • Gram-negative bacteria are intrinsically resistant due to efficient bacterial efflux pumps.
    • Resistance in Gram-positive bacteria (e.g. MRSA) is due to decreased Linezolid uptake and the presence of methyl transferases.

    Macrolides

    • Alternatives to penicillins and cephalosporins.
    • Used for treating Chlamydia, Mycobacterium avium complex (MAC), and pneumonia (CAP)/upper/lower respiratory infections in patients with penicillin allergies.
    • Examples: azithromycin, erythromycin.

    Chlamydia trachomatis

    • Gram-negative coccoid bacterium causing chlamydia infections and koalas
    • Can cause complications like pelvic inflammatory disease if left untreated.

    Macrolides (Erythromycin, E-mycin)

    • Macrolide antibiotics, containing a large lactone ring and desosamine/cladinose sugar units.
    • Isolated from Saccharopolyspora erythraea.
    • Similar spectrum to penicillins used as alternatives to penicillins in cases of penicillin allergy.
    • Often used as HCl salts to improve absorption.
    • Ester prodrugs mask the bitter taste and increase solubility.

    Chemical Deactivation of Erythromycin

    • Acid instability of Erythromycin overcome using enteric coatings.
    • Water-insoluble dosage forms (like stearate salt) improve absorption and mask bitterness.

    Erythromycin

    • Macrolide antibiotic that blocks the exit of nascent proteins from the ribosome by binding to high-affinity sites.
    • Drug acts by inhibiting protein elongation and disrupts the dissociation of peptidyl-tRNAs from the ribosome.
    • Main components of binding pocket is nucleotide 2058 which in bacteria is adenine - and macrolides strongly bind to this nucleotide in eukaryotic cells.

    Resistance to Erythromycin

    • Resistance is due to modifications of the bacterial ribosome specifically a methylase.

    Tuberculosis (TB)

    • 90% of the world's exposed population have developed latent TB.
    • One new infection occurs ≈ every second (7-9 million annual new cases).
    • TB is caused by Mycobacterium tuberculosis.
    • MDR-TB (multi-drug resistance) and XDR-TB (extensively drug-resistant tuberculosis) have emerged as significant challenges in TB treatment due to bacterial mutations.
    • Treatment regimens for TB usually involve a combination therapy. The process is lengthy and complicated.

    Mycobacteria

    • Aerobic organisms with thicker cell walls resulting in higher resistance to many common antibiotics like beta-lactams.

    Isoniazid (isonicotinoylhydrazine, INH)

    • Active against TB, found to be an effective medication for TB treatment.
    • Activated by mycobacterial catalase-peroxidase (KatG), which complex with NADP.
    • Inhibits protein reductase by preventing access to natural substrates.
    • Parts of mycobacterial type II fatty acid synthase system (FAS-II) which results in long-chained mycolic acids.

    Resistance to INH

    • Resistance to INH can result from mutations in KatG, overexpression of InhA gene and increased N-acetyltransferase activity.

    Anti-fungal Agents

    • Increased fungal mycoses incidence in immuno-compromised patients.
    • Fungi are eukaryotes and selective agents for treatment presents greater challenges.
    • Ergosterol levels are different in fungi compared to mammals, meaning this sterol is suitable for targeting.

    Candida albicans

    • Common commensal yeast in the GI tract.
    • Can become pathogenic in immunocompromised patients (e.g., those with HIV) leading to episodes of candidiasis.

    Anti-fungal Agents (Amphotericin B)

    • Disrupts fungal cell membranes by binding to ergosterol.
    • Low selectivity means it also toxic to mammalian cells (containing cholesterol).

    Azoles

    • Imidazoles and triazoles (e.g., ketoconazole, clotrimazole, fluconazole, itraconazole, posaconazole, voriconazole), are anti-fungal agents inhibiting sterol synthesis.

    Azoles - Mechanism of Action

    • Azoles inhibit lanosterol 14a-demethylase (CYP450), which is essential for ergosterol biosynthesis, in fungal cells.
    • Lanosterol 14a-demethylase (CYP450) removes a methyl group from lanosterol.

    Azoles - Selectivity

    • Active site conformations of the target enzyme differ between fungi and mammals resulting from altered ergosterol synthesis in fungal membranes.

    Azoles - Resistance

    • Active efflux of azoles occur in species like Candida due to overexpression of ERG11, which codes for lanosterol 14α-demethylase.

    Azoles - Drug Interactions

    • Azoles inhibit CYP450 activity and are substrates for same, so they may alter the metabolism of other drugs resulting in increased or decreased effects.
    • Monitor INR (International Normalized Ratio) and modify warfarin dose as required to minimise bleeding risks.

    Summary

    • Antibacterial/antifungal resistance arises from drug modification, target modification, increased levels of drug targets and reduced accumulation or increased efflux.

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