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INFECTION AND IMMUNITY - Coggle Diagram

- - - - IN DETAIL
        
        CELL WALL SYNTHESIS TARGETTING
        
        Target peptidoglycan. B-lactams bind to the traspeptidase enzyme(pbp) which is essential for crosslinking.
        
        On the other hand, Vancomycin binds to the peptidoglycan itself. Some( cycloserine,phosphomycin) inhibits the precursors of peptidoglycan
        
        cidal only against growing cells
        
        Structure of peptidoglycan- 1) backbone- NAG bind a-1,4 to NAMA. 2) Crosslinking- order(l ala,d glu,dap,d ala). upside down DAP binds to D-ala. 3) Prior to crosslink it ends with d ala, d ala
        
        PROTEIN SYNTHESIS INHIBITORS
        
        1) Macrolides-erythromycin,clarithromycin
        
        Binds to 50s and prevents exit of polypeptide through tunnel
        
        2) Tetracyclines- tetracycline
        
        Bind to 30s and prevent binding of trna to ribosomal complex.
        
        3) Aminoglycoside- streptomycin
        
        Binds to 30s and causes misread of codon and interferes with initation complex
        
        CYTOPLASMIC MEMBRANE STRUCTURE-cyclic lipopeptides
        
        Polymixin (+ve charge)- interacts with the negatively charged lps also could cause leakage-> intracellular targets
        
        Daptomycin(-ve charge)- inserts into lipid membrane-> submic and supramic
        
        DNA DEP RNA POLYMERASE
        
        Semisynthetic(Rifampicin)-> bind to polymerase to prevent formation of mrna. cidal and broad. Crosses the bbb.
        
        for mycobacterial infections, prophylaxis of meningococcal
    - - How do we have ineffective treatments?- resistance, time for complete killing increased, treatment errors(too short,low dosage)
        
        RESISTANCE- driven by antibiotic use and natural selection and resistance might not have been present in clinically important species( from other species)
        
        Resistance organism-> growth will not be inhibited by achievable antibiotic conc
        
        Multi Drug Resistance(MDR)- resistant to atleast 1 agent in 3 or > antimicrobial categories
        
        Extreme drug resistant(xdr)- " " in all but 2 or less categories
        
        Pan drug resistant- all and all resistant
        
        Intrinsic-naturally resistant bacteria,poor antibiotic uptake. Acquired resistance-genetic uptake,altered expression+ mutations affecting target molecule
        
        MECHANISMS OF RESISTANCE
        
        efflux pumps(b lactams, aminoglycosides)
        
        -bacteria uses efflux pump(intrinsic) to remove toxic compounds. ABC,MFS abccp,MATE afc-> g+ve. g-ve= RND, ABC(macrolides)
        
        block penetration- lactams, tetracyclines
        
        many hydrophilic antibiotics enter via porins or channels.
        
        no porin, reduced expression and narrow channel
        
        Inactivation- lactams, amino
        
        degrade enzyme-> b-lactamases-> changes b lactams
        
        we can use beta lactamase inhibitor(clavulanic acid, in conjunction with b-lactam. Thus saves the antibiotic from degradation by mimicing the beta lactam .
        
        1 more item...
        
        target modification-rifam,vanco
        
        ex. streptomycin and spectinomycin-> addition of phosphate group. Mutations must leave enzymes to function.
        
        Van A gene changes D-ala,D-ala to D-ala D-lac. Vancomycin cannot bind.
        
        WHAT CAN WE DO?
        
        1) Best practice presciption
        
        30-50% not used properly. Antibiotics used in livestock often not for treatment(prophylactic and sub therapeautic doses)-> cheaper+ vaccine
        
        2) combination antibiotics
        
        additive-> straight add effect(1+1)
        
        synergistic->higher when we add 2. (1+1)>2. au.baimanni
        
        -Polymyxin treatment permeabilizes cell membranes, which increases access of other
        antibiotics to intracellular targets.
        
        Protein synthesisinhibitor reduces production of carbapenemase enzymes therefore
        improving the action of the carbapenems
        
        Antag-lower when added
        
        3) New antibiotics
        
        4) Phage therapy
      - OTHER STUFF
        
        WHO classification of antibiotics(Aware)
        
        Access- generic(no incentive), shortages in high income countries+ counterfeit in low income
        
        Watch-generic( no incentive)
        
        more readily available
        
        Reserve-expensive
        
        Not reccommended
        
        Bacteriophages are not game changers(immunological neutralization of phages)
        
        FACTORS AFFECTING ANTIMICROBIAL DEVELOPMENT
        
        1) Scientific difficulty
        mode of action
        activity spectrum
        
        2) Economic return on R and D investment(-ve)
        reserved antibiotics
        
        Phase 3 studies for anti mdr antimicrobials. Non- inferiority trials against common pathogens.
        
        mostly at small institutions, no incentive to invest in antimicrobial r and d. Cost of antimicrobials exceed revenue
        
        1 more item...
        
        Thus
        
        Pull initiatives
        
        -england- pfizer and shionogi 10 million euros per year guarenteed
        -eu- 1 year of exclusive sales of another drug
        -US- PASTEUR
        
        MODELS
        
        2 more items...
  - - - Ergosterol- unique to fungi and protozoa. synthesis of it is targetted by azoles and terbinafine. Membrane permeability affected by amphotericin b, nystatin.
- - - - gram negative,aerobic,non motile, cocco
        
        survives well in environment and develops resistance
        
        opportunistic pathogen-> thus occurs in hospital setting
        
        Multi drug resistant (50-70% resistant to carbapenems)
    - - Beta lactamases- has all 4 classes of lactamases( metallo, ampc, oxallo, carbapenamase)
      - efflux-> tetracycline efflux
      - reduced expression or inactivation of porins(transposons). CarO
      - aminoglycoside modifying enzymes- acetyl,adenyl,phospho. Horizontally acquired
      - Target altering, gyrase(gyrasea) and pbb
      - Multiple Resistant Mechanisms- for beta lactams- efflux,modify pbp,lactamases.
        for colistin-> loss of lps
        for aminoglycoside -> AME degradation,efflux,ribo protein
        for quinolones->mutation in gyrase+ efflux
        
        Colistin(+ve charge)- Last line of treatment( positively charged, fatty acid tail) destabilizes g-ve outer membrane.
        
        Resistance to colistin(how?)
        
        1) Complete LPS loss-
        via mutations in ipxa( a single base change in this gene causes this-deletion of T),c,d.
        
        2) Addition of phosphoethanolomine to lps(PETn)- mutations in pmra and pmrb and increased expression of pmrc
        
        pmrc-> increases positive charge in lps -> less interaaction with colistin
    - - Combinatorial methods:
        -polymixin with rifampicin,tigecycline,azithromycin
  - - - -skin commensal
        
        after resistance to penicillin-> methicilin but we got mssa and mrsa
        
        resistance via mecA gene(horizontal tranfer) which encodes a different pbp
    - - Vancomycin-> crticial treatment option
      - Combination treatments- Rifampicin+ Fusidic acid(protein synthesis,elongation factor Ef-Tu)
      - Linezolid(protien synthesis inhibition)
    - - Vancomycin intermediate SA(VISA)- thickened cell wall + reduced cross links
      - Vancomycin resistant SA(VRSA)- plasmid mediated+uncommon
  - - - Isoniazid- A pro drug which targets cell wall synthesis. Activated by Katg to isonicotinic acyl nad.. Inhibits fatty acid synthesis. Resistance due to mutations in Katg.
      - Pyrazinamide- prodrug which is converted by pyrazinamidase(myc enzyme) into pyrazinoic acid. maybe fatty acid synthesis
      - Ethambutol- prevents conversion of arabinose to arabinogalactan
    - - 1) Sustained political+finance commitment
        2)Diagnosis by quality sputum smear tech
        3)treatment given under direct observation
        4)regular uninterrupted supply of high quality anti tb drugs
        5) Standard recording+ reporting
        6) Testing for cure
      - however
        
        MDR- TB AND XDR-TB
        
        mdr-tb-> resistant to isoniazid,rifampin
        xdr-tb-> resistant to isoniazid and rifampin, plus any fluoroquinolone and at least one of three
        injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin). cure is very hard(30-50%)
- - - - SPANISH FLU
        
        -to resurrect it, 6 plasmids,+ 2 plasmids with ha and na strains.
        
        Upper respiratory tract a2-6 but inner is a2-3. I t causes prolonged inflammation via cytokine storm
      - Swine origin- Influenza A
        
        H1N1, but antigenically different
        
        deaths were due to secondary bac infections or those who were preg,medical conditions. Dosent affect ages above 65, possibly due to the production of antibodies due to previous strain
        
        Bird flu(h1n1/h7n9)
        
        low pathogenic avian influence(lpai)
        minor+no symptoms
        
        HPAI.haemorrage,very virulent
        
        Characteristics- insertion of aa into cleavage site -> more efficient cleavage by furin+plasmid
        direct transmission from birds to humans, no need of pigs. endemic in wild aquatic bird. But it cant spread from human to human yet.
        
        SARS-COV 2(beta)
        
        Cycle- after entry via attachment-> +rna genome-> rna dep rna poly-> replicate. translated at specific locations to get different proteins(M,N,S-attachment) to RER passing through golgi gives the virus
        
        chinese horshoe bats-pangolins-humans
        
        outbreak in wuhan-> linked to wet market. spread from racoon dogs+unknown birds
        
        1 more item...
        
        MERS-ncov outbreaks
        
        Intermediary host have big roles- camels,meerkats
        
        Features-It has receptor binding domain+ polybasic cleavage site. The domain binds to ACE2 receptors.
  - - - Influenza- M2(uncoating),NA(neuraminadase-breaks)(release),HA(attachment)
        
        HA is a trimer recognising sialic acid. When sialic acid bonds to galactose we can either have a2-6 linkage(humans) or a2-3(bird viruses). galactose is the part of the virus.
        
        HA is the key for penetration+ uncoating and is cleaved to get activated by trypsin like protease
        
        Inffluenza epidemic-aerosol.droplet, virus shed before onset of symptoms.
        
        Induces a robust immune response- fever,pneumonia,(TNF). Generates antibody response to spike protien(HA>NA), Tcell responses
        
        -ability to spread from human to human.
        -favourable mutations
        
        At risk- young, elderly or immunocompromised. Adaptive protects by b cell(antibodies), cd4 cells(matures the adaptive response) and cd8(against virus by target conserved peptides)
      - makes it dangerous
        
        ANTIGENIC DRIFT-mutation in genome which affects binding( HA)-> thus previous years strain is not effective.
        
        H3N2+H5N1-> H5N2(highly virulent)
        
        mutations can sometimes neutralize antibodies