BIO2078 L9 - Lecture notes 9 PDF

Preview

Summary

Antibodies...

Description

21st October 2019

BIO 2078 – Medical and General Microbiology Lecture 9 – Antibiotics 3 modes of action: Bacteriostatic

Bacteriocidal

Bacteriolytic

Time

Macrolides = bacteriostatic antibiotics that inhibit protein synthesis. - 12- to 16-member macrolactone rings decorated with various amino-sugars. - The macrolide-binding site is the large ribosomal subunit in the upper part of the nascent peptide exit tunnel. - Easy passage of the newly made protein through the tunnel is crucial for protein synthesis. - Binding of the macrolide antibiotics in the tunnel impedes progression of the nascent peptide and results in a general inhibition of translation. Fluoroquinolones = bacteriocidal  Targert DNA gyrase (topoisomerase II) and topoisomerase IV.  Passive diffusion into Gram +ves and via outer membrane porins in gram -ves.  Newer fluoroquinolones have a broader spectrum and a better activity against more gram +ves.  Second most used antibiotics  Synthetic antimicrobial Cephalosporins = broad spectrum, semi-synthetic beta-lactam, bacteriolytic antibiotics derived from the mould, Cephalosporium.

21st October 2019

They are chemically related to penicillins and have the same mechanism of action – interfering with bacterial cell wall synthesis.

There are new antibiotics coming into phase 2&3 of clinical trials, that will be coming onto the market soon. There are 39 undergoing trials, of which 25 are in phase 2&3, and 3 which are under review at the FDA. FAB = fatty-acid biosynthesis. These new drugs take aim at inhbiting a broad range of targets in bacterial pathogens, including topoisomerase, protein synthesis, cell membranes, and the cell wall. These include -lactamase inhibitors to overcome enzymatic inactivation of -lactam antibiotics. Several companies are evaluating novel inhibitors of Clostridium difficile, a pathogen that disrupts the gastrointestinal tract. Phage as antimicrobials: Stages of infection - Adsorption to specific receptor – phage attachment to is highly specific - DNA injection – the DNA of lytic phages is transferred into the cell after peptidoglycan degradation and pore formation in the bacterial cell. - Redirection of host metabolism to phage DNA replication and phage protein synthesis. - Assembly and packing of phage particles - Bacterial cell lysis and phage progeny release – phage late proteins including lysins, holins or murein synthesis inhibitors are responsible for host cell lysis and virion burst to the environment. ADVANTAGES of lytic phages:  Specific  Cheap DISADVANTAGES:  Narrow spectrum  Bacterial resistance Alternative phage strategies use phage to deliver a protein that interferes with an essential bacterial process rendering the bacteria more susceptible to antibiotics.

21st October 2019

Engineer clusters, regularly interspaced, short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system, naturally employed in bacteria as a defence strategy against mobile elements, i.e. make RNA guided nucleases. Enzybiotics are derived from endolysins, bacteriophage-encoded enzymes that lyse the infected bacterial cell at the end of the lytic replication cycle.

Anti-virulence strategies inhibit specific mechanisms that promote infection and are essential to persistence in a pathogenic cascade and/or cause disease symptoms. They offer a reduced selection pressure for drugresistant mutations. Virulencespecific therapeutics would avoid the undesirable dramatic alterations of the host microbiota that are associated with current antibiotics. Bacteria bind to superficial facet cells on the surface and create IBCs (intracellular bacterial communities), which are essentially biofilms inside a cell. They then replicate until they burst out of the cell and spread to new cells, including underlying transitional cells. Pilicide is a anti-virulence strategy that kills the bacteria’s pili, therefore preventing binding from being able to take place, and protecting against infection within the host. Chemical structures of anti-adhesive carbohydrate ligands. (A-C) ligand for the FimH adhesin and (D) for the PapG adhesin.

Quorum sensing controls a range of phenotypes including virulence, reporter strains used for the identification of inhibitors. These inhibitors can reduce the activity of the AHL receptor or synthase or degrade the AHL. They can even mimic the signal molecules primarily by using synthetic compounds.

21st October 2019

Targeting toxins: Virstatin was discovered by monitoring ToxT expression, ToxT is a transcription factor in V.choleraea and is responsible for toxin production. Receptor mimics can bind to host toxin receptors, preventing binding to actual toxins.

Another anti-virulence strategy is inhibiting secretin systems. These secrete virulence factors for several pathogens. Nearly all the inhibitors discovered a lack of potency and a clear mode of action. To address this problem, the ATPase YscN, which is essential for T3SS activity in Yersinia pestis, has been targeted.

Inhibiting secretion systems: 62 genes upregulated, 76 downregulated. Of these 76 that are repressed, 29 (38.2%) are involved in Salmonella host cell invasion, clearly demonstrating that a major effect of the gut metabolome on Salmonella is repression of invasion.

Synergistic drugs suppress drug-susceptible subpopulations more than single drug therapies however, this eliminates competitors of the drug-resistant cells, allowing them to grow more rapidly than the normal bacterial cells would have at weaker synergies. Thus greater synergies can increase population densities, where antibiotic resistance is present....