Chemotherapy

Natural Resistance:

• Organism lacks stucture that the antibacterial inhibits
• Cell wall/membrane of organism may be impermeable to antibiotic agent

Levels of Antibiotic Resistance: 

• Partial (low level or intermediate)  - can be overcome by increasing dose of antibiotic or combining with a second agent
• Complete resistance

Developed Resistance:

• Enzymes modification or destruction of antibacterial agent
• Modification of target of antibiotic
• Change in metabolic pathway that the antibiotic affects
• Organism may pump (efflux pump) the antibiotic out of cell
• Altering the permeability of cell wall to antibiotic

B-lactamase enzyme (penicillinase) can be found in Gram positive and negative bacteria

- They act by catalytic disruption of the cyclic amide bond -> breaking the ring

- Provide multi-resistance to β-lactam antibiotics such as penicillins

Modification of Target:

• Aminoglycosides - alteration on protein of 30S subunit of the ribosome
• Erythromycin - alteration of the binding site on 50S subunit of the ribosome
• Fluoroquinolones - point mutation. in the DNA gyrase A protein

Interferance with Antibiotic Pathway:

• Methicillin - production of a modified transpeptidase
• Sulfonamide - produce a form of dihydropteroate synthetase which has a low affinity for drug - some affinity for PABA
• Trimethoprim - synthesis of a dihydrofolate reductase with a low/zero affinity of the drug

Organism may (Efflux) Pump Antibiotic out of Cell:

• Tetracycline - protein within membrane which promote energy dependent efflux pump
• Erthromycin & Fluoroquinolones - energy dependent efflux

Altered Permeability:

• Involving outer membrane of gram negative organism
• Thickening of peptidoglycan in gram positive organism

Genetics of resistance -> chromosomal mutation resilting in resistance to a class of antimicrobial

• single chromosomal mutation resulting in synthesis of altered protein
• series of mutations

Causes of Chromosomal Mutations:

• misuse of antibiotic
• exposure to antibiotic in nature

Transmission of Gene of Plasmid:

• aquired resistance - resistance to different antibacterials
• some plasmids cross species barrier

Resistance acquired from transposon and other mobile elements:

• Transposon (jumping genes) - can intergrate into either chromosome or plasmid
• Transposon can carry more and more resistance gene
• Can hitch-hike on plasmid

Cassette of resistance:

• Consist of multiple resistance gene may come together in structure known as intergron
• Encode site specific recombination of enzymes (intergrase)

Transfer of resistance gene between bacteria:

• Plasmid, transposon or gene cassette need to be transmitted between bacter via bacterial transformation (donor cell releases DNA into environment, picked up by receptor on recipient cell), bacterial transduction (phage-infected donor cell releases phage, picks up resistant bacteria and infects recipient cell), and bacterial conjugation (donor cell trasmits DNA on plasmid and cells join)

• Prevent dispensing antibiotics without a prescription
• Limit use of antibiotics in industry 
• Avoid misuse of antibiotics - inadequate indications
• Follow antibiotic policies
• Surveillance of antibiotic use coupled with monitoring emerging patterns of resistance

• Antibiotic resistance has been increasing but is slowly levelled out
• Resistance genetic - chromosomal mutation & transmission of gene via plasmid, transposon, cassette
• Natural resistance - lack structure or impermeable to antibiotic
• Developed resistance - enzyme modification/destruction of antibiotic, modification of target of antibiotic, change in bacteria pathway, efflux pump