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?

Acylase from E. coli Signup and view all the answers

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

The mold cannot produce any penicillins. Signup and view all the answers

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

Preventing crosslink formation of bacterial cell wall components. Signup and view all the answers

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

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

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

Linezolid Signup and view all the answers

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

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

How do altered ligases contribute to the resistance against vancomycin?

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

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

Antibacterials are generally used for acute conditions. Signup and view all the answers

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

Griseofulvin Signup and view all the answers

Which type of antibacterial agent inhibits cell growth?

Bacteriostatic Signup and view all the answers

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

Bacterial cells have defined nuclei. Signup and view all the answers

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

Escherichia coli Signup and view all the answers

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

They are reserved until older classes are ineffective. Signup and view all the answers

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

Macrolides Signup and view all the answers

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

Prokaryotic cells have cell walls. Signup and view all the answers

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

They enhance the bactericidal activity by facilitating membrane interaction. Signup and view all the answers

What feature characterizes daptomycin's chemical structure?

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

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

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

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

Thickened cell walls preventing diffusion into the membrane. Signup and view all the answers

How does daptomycin interact with the cytoplasmic membrane?

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

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

Introduction of additional peptidoglycan layers. Signup and view all the answers

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

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

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

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

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

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

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

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

What characterizes chloramphenicol in terms of its antibacterial properties?

It is highly lipophilic and can penetrate most tissues. Signup and view all the answers

Which side effect is a significant concern when administering chloramphenicol?

Aplastic anaemia due to bone marrow suppression. Signup and view all the answers

In which clinical scenario is chloramphenicol particularly used?

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

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

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

What role do CAT genes play in antibiotic resistance?

They can be found on both plasmids and chromosomes. Signup and view all the answers

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

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

What role do variations in R′ play in sulphonamides?

They are responsible for the different sulphonamides used clinically. Signup and view all the answers

What is the consequence of sulphonamides being incorporated into macromolecules?

They inhibit further synthesis of folic acid. Signup and view all the answers

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

It binds PABA and initiates the synthesis process. Signup and view all the answers

What can reverse the incorporation of sulphonamide into macromolecules?

The introduction of additional PABA. Signup and view all the answers

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

Increased activity compared to other sulphonamides. Signup and view all the answers

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

Poor ionization leading to potential kidney blockages. Signup and view all the answers

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

They share similar molecular dimensions and properties. Signup and view all the answers

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

It decreases the pKa and increases ionization. Signup and view all the answers

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

Variation in substituents at specific positions. Signup and view all the answers

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

The presence of pyrophosphokinase (PPPK). Signup and view all the answers

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

It enhances the binding of sulphonamides to enzymes. Signup and view all the answers

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

It releases the active amino group within the body. Signup and view all the answers

What happens when excess PABA is present in the reaction?

Folic acid formation can resume. Signup and view all the answers

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

Hydrogen bonds and ionic bonds. Signup and view all the answers

Study Notes

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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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Test your knowledge on the fermentation processes involved in antibiotics production, focusing on penicillin and vancomycin. This quiz covers mechanisms, resistance, and the structural aspects of these crucial compounds. Perfect for students in microbiology and pharmaceutical sciences.