Antibiotics PDF

Ideal Properties of an Antibiotic 1. Must impede growth of pathogenic bacteria o Bacteriostatic (slows/prevents growth - favourable as it doesn't induce such a large immune response) vs Bactericidal (kills bacteria) o Narrow spectrum vs broad spectrum...

Ideal Properties of an Antibiotic 1. Must impede growth of pathogenic bacteria o Bacteriostatic (slows/prevents growth - favourable as it doesn't induce such a large immune response) vs Bactericidal (kills bacteria) o Narrow spectrum vs broad spectrum Personalised medicine is difficult in infection due to how long it takes to identify microorganisms (~48hrs) and to check for antibiogram (test of antibiotic resistance) (~72hrs total) Empirical treatment - treating before knowing the full information - use of broad- spectrum drugs. Broad-Spectrum drugs are also more readily available due to cost/profit ratio of drug development of personalised drugs (i.e. less profit from drugs only suitable for less people). 2. Selective toxicity o Most antibiotics used are B-lactams - target cell wall itself or apparatus (enzymes) which synthesise bacterial cell wall. Humans don't have cell wall, therefore low toxicity in humans. o Some antibiotics target DNA synthesis, RNA synthesis, membranes. Humans have similar apparatus so therefore can be toxic to humans. Other regions on enzymes can be targeted to overcome toxicity. 3. Good Bioavailability is different for different microorganisms 4. Pharmacokinetics also different for different microorganisms 5. Low cost 6. Stability (i.e. easy storage, administration etc.) How do antibiotics work? Most antibiotics bind to enzymes to disrupt cellular processes Binding can be permanent (but is inefficient) More efficient antibiotics bind to enzyme domain, change the domain then bind to another enzyme - dosing doesn't need to be as high Sometimes drugs cannot bind to active domain (e.g. in cases such as RNA polymerase where it is too similar to human active site)  o Binding to another area of the enzyme (e.g. structural area) which is not the same as a binding site in human enzyme changes the overall shape of the molecule changes the shape of the catalytic domain and reduces binding efficiency to substrate Sometimes the substrate and drug both bind to enzyme Alternative antibiotic MOAs e.g. efflux pumps exist Efflux pumps have not evolved to resist antibiotics, their purpose is to remove toxic substances Drugs which bind to efflux pump prevent removal of toxin in bacterial cells, eventually leading to cell death How Are Antibacterials different to other types of pharmaceuticals? Typically acute conditions (Most other diseases have insidious onset & are degenerate) Rapid pathological effects Variety of body site Variety of pathogen physiologies Variety of pathogen survival strategies (E.g. tolerance, biofilms) Host-pathogen interaction may affect crucial organs Eradication of commensal flora Secondary effects of treatment Diagnostic gap (i.e. time taken to get in depth diagnosis) Resistance Short term vs long term toxicity Targets of Antibiotics  Cell membrane Cell wall Nucleic acid synthesis Protein synthesis Bacterial metabolism Protein Synthesis Inhibitors Many parts of the central dogma can be targeted and interrupted by drugs to inhibit protein synthesis  Blue boxes: antibiotics inhibiting particular process of protein synthesis However small and large subunits of ribosome are similar in prokaryotic and eukaryotic cells (almost same sequence identity) Oxazolidinones Binding sites on 30s and 50s ribosomal subunits with interactions with proteins and RNA Prevents complex formation of the 2 ribosomal subunits: o MOA: Binds on to large ribosomal subunit preventing effective association with initiation complex (small ribosomal subunit with tRNA) Bacteriostatic Activity restricted to Gram positive organisms as it is effluxed via the AcrAC-TolC efflux system in gram negatives - concentration in gram negatives is never high enough for therapeutic effect Not natural product (100% synthetic) Clinical use: o Linezolid us used sparingly as an IV or oral agent in treatment of gram+ infections, specifically: Bacteraemia  Pneumonia Skin and soft tissue infection Already has clinical resistance in Enterococci and Staphylococci: o Resistance found in lab-derived and clinical isolates of staphylococci and enterococci o Loci found to be in the V domain of the 23S rRNA (structural RNA) in the 50S ribosomal subunit - changed shape of ribosome, hiding binding pocket leading to less effective binding o Selection of resistance is clinically rare due to the multi-copy nature of 23S rRNA in enterococci (i.e. there should be ~4-7 copies of 23S rRNA gene, a single point mutation is unlikely to lead to enough of a change to show clinical resistance) but the occurrence of resistance is increasing (especially in enterococci) o G2576T is the mutation found in clinically isolated resistance S. aureus and enterococci o Homologous recombination: Under stress bacterial cells chop up genome and swap it around to potentially increase survival. Spontaneous mutation: