ANTI-MICROBIALs -Removal and resistance

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ANTI-MICROBIALs -Removal and resistance by Mind Map: ANTI-MICROBIALs -Removal and  resistance

1. Defintions

1.1. Antibiotic: antimicrobial substance made by a micro-organism

1.1.1. Fungi : Penicillium, Cephalosporium

1.1.2. Actinomycetes : Streptomyces, Micromonospora

1.1.3. (Soil bacteria) e.g streptomycin, gentamicin.

1.2. Antimicrobials : antibiotics AND chemically synthesised substances

1.2.1. e.g. sulphonamides, quinolones (ciprofloxacin etc.)

1.3. *Bactericidal = kill bacteria (some conditions)

1.4. Bacteriostatic = Stop growth/multiplication

1.5. *beta lactamase = enzyme which cleaves b lactam ring

1.5.1. (usually secreted in presence of antibiotics)

2. Anti-bacterial targets

2.1. 1. Cell wall synthesis

2.1.1. Beta lactams*, Penicillin Benzylpenicillin (penicillin G) Phenoxymethylpenicillin (penicillin V) Ampicillin/Amoxicillin Flucloxacillin Piperacillin Cephalosporin Info LAME Types PBP Catalysis of transpeptidation by PBP in cell wall Transpeptidase crosslinks the peptidoglycan net in the cell wall of Gram-positive bacteria B lactam MOA Peptidoglycan (PGN) Carbapenems modified thienamycins from Streptomyces (no sulphur molecule) for resistant Gram negative, Gram positive (not MRSA) Injection only: meropenem, imipenem, ertapenem Resistance Removal of Drug: Inactivation of Drug: Alteration of Target: Reduced intracellular penetration, HOW?

2.1.2. Glycopeptide* Vancomycin Bind alanine subunits and prevent incorporation into PGN polymer

2.1.3. Bacitracin interferes with PGN transfer to the cell wall by inhibiting dephosphorylation of lipid carrier

2.1.4. Cycloserine structural analog of D-alanine and competes and inhibitd incorporation of D-alanine into peptidoglycan

2.2. 2. Protein synthesis

2.2.1. Acting on the bacterial ribosome 50s 23srRNA 5srRNA 30s 16srRNA

2.2.2. Tetracyclines Target: Gram positive and Gram negative Side effects/toxicity Deposited in growing teeth/ bone Contraindicated in children and after 16th week of pregnancy Photosensitisation Hepatotoxicity Resistance Widespread resistance mainly efflux and ribosomal protection Tigecycline Tetracycline derivative new broad spectrum agent active against resistant Gram positive and negative bacteria IV only

2.2.3. Macrolides Source: Prototype erythomycin from bacterium Saccharopolyspora erythraea Types Erythromycin Clarithromycin Azithromycin Target: Chlamydia, Rickettsia, Legionella Act on Gram positives, Mycoplasma Azithromycin additional Gram negative activity Administration: Oral and IV Side effects: Interact with statins, risk of myopathy Immunomodulators increase gastric motility

2.2.4. Aminoglycosides* Natural products from soil bacteria Actinomycetes : Streptomyces, Micromonospora 1990s reduced use as fluoroquinolones Types Streptomycin, Gentamicin MOA: bind 30s Ribosomal subunit Misincorporation of Amino Acids into elongating peptides Uptake requires Cytochrome mediated membrane potential

2.2.5. Oxazolidinone Linezolid TB

2.3. 3. Nucleic acid synthesis/replication

2.3.1. Synthetic antibacterials (types) Rifampicin -Trimethoprim/sulfa Quinolones* Oxazolidinones (Linezolid) Source MOA Side Effects Target Admin

2.3.2. Inhibition of DNA replication Quinolones (topoisomerase IV and DNA gyrase) Source MOA Side Effects Target

2.3.3. Inhibitors of RNA polymerase (mRNA synthesis) Rifampicin Source MOA Side Effects Target

2.3.4. Antimetabolites inhibiting precursor synthesis Antifolates (Sulphonamides, trimethoprim) Bacteria make, but do not take up folate (B9) Metronidazole (anaerobic infections only) Source MOA Side Effects Target

2.4. 4. Essential Metabolic pathways

2.5. 5. Cell membrane functions

2.5.1. Cell Membrane Polymyxin Gram Negative Topical due to cell membrane issue

2.5.2. Lipopeptides Daptomycin Source MOA Target Side Effects IV only – reserve agent

2.5.3. Colistin

2.5.4. Azoles (Fungi)

2.5.5. Amphotericin B (Fungi)

2.6. Resistance

2.6.1. Removal of Drug: Gram negatives, Outer membrane

2.6.2. Inactivation of Drug: Gram neg and Gram pos (bacterial beta lactamase enzyme hydrolyses the drug)

2.6.3. Alteration of Target: Gram positives (MRSA, PBP2a)

2.6.4. Reduced intracellular penetration,

2.6.5. HOW? Local selection of mutation Chromosome Horizontal transfer of resistance Plasmid (conjugate,plasmid spread) Transposon (gene spread) Phage? Resistance genes preceded therapeutic antibiotics Present in environment e.g. soil. Antibiotics seen as a subset of small inter-bacterial signalling molecules therapeutic use important selecting force interpersonal spread of resistant bacteria is significant The more an antimicrobial is used, the more selection pressure is exerted for the spread of resistance genes/resistant organisms Indiscriminant use of antimicrobials risks rendering some common pathogens untreatable