Antimicrobial MoA and resistance mechanisms

• what are the 3 requirements for activity?

  1. adsorption to cell surface = must be wet so needs contact time

  2. passage into cell = outer surface structure affects sensitivity to disinfectants

  3. interaction with target = specific targets (organelles)

  
• what are the 4 different antimicrobial MoAs?

  1. oxidation

  2. crosslinking

  3. coagulation

  4. disruption of structures

  
• example compounds that undergo oxidation?

  peroxygen compounds and some halogens
• describe 3 mechanisms of oxidation

  1. strand breakage by binding to DNA/RNA = disrupts transcription/translation/replication

  2. rxn and degradation of unsaturated FAs in membranes = leaky membranes

  3. modification of S-S bonds in proteins = loss of structure disrupts enzymes
• examples of compounds that undergo crosslinking

  aldehydes, phenols, ethanol, QACs, chlorohexidine
• name 2 crosslinking mechanisms

  1. aldehydes cause crosslinking of lysine residues to other AAs - changes protein structure + protein aggregation

  2. crosslinking of DNA, RNA/proteins/PG
• examples of compounds that undergo coagulation

  chlorohexidine, phenols, ethanol, QACs
• what is the mechanism of coagulation?

  macromolecule denaturation = extensive coagulation and precipitation (disrupts cytoplasm)
• examples of compounds that undergo disruption of structures

  QACs
• what are the 2 mechanisms of disruption of structures?

  1. cation's affinity for -vely charged microbial membranes = disrupts H+ motive which disrupts membrane-associated activities

  2. directly bind to/damage lipid membrane = indirectly bind to LPS
• what are the 2 types of mechanism?

  1. intrinsic = natural chromosomally encoded property

  2. extrinsic = organisms become resistant
• what are the 2 subtypes of resistance?

  1. phenotypic = response to mode of growth (REVERSIBLE)

  2. genetic = mutation (IRREVERSIBLE) + genetic transfer
• what are efflux pumps?

  - example of innate resistance

  - pump antimicrobials out of cell via pumps in cell wall

  - chromosomally encoded pumps confer natural low resistance level all the time

  
• name the 2 mechanisms of innate immunity

  1. barrier to penetration = spore, waxy FAs, outer membrane, PG

  2. decreased accumulation = efflux, absence of target
• what are the 2 phenotypic mechanisms of acquired resistance?

  1. intracellular bacteria = Legionella causes Legionnaire's disease, exists as parasite within protozoa - isolated from water sources

  2. biofilms = physical barrier that facilitates cell-cell communication and genetic exchange
• what are the 2 genotypic mechanisms of acquired resistance?

  1. chromosomal mutation = changes in protein/AA/phospholipid composition, changes in number/size of porins, increased efflux

  2. multi-drug resistance plasmids = co-resistance - selection for resistance by one AM will also select resistance for every compound encoded on plasmid
• how do you effect efflux?

  - partly under control of mar operon

  - inactivation of marR (activator) or overexpression of marA (repressor) increases efficiency
• how can one reduce resistance?

  1. strict cleaning/disinfection policies

  2. trained staff

  3. disinfectant rotation

  4. effectiveness monitoring
• what is the infection chain?

  1. pathogen

  2. reservoir

  3. portal of exit

  4. mode of transmission

  5. portal of entry

  6. susceptible host