Intrinsic resistance refers to resistance which is an inherent and unchanging property of a particular organism. • Acquired resistance refers to the appearance of resistance in organisms which were initially susceptible to a particular antibiotic.
Low level resistance: when an organism becomes resistant to the normal clinical dose of the antibiotic but may be treated by the use of higher doses. • High level resistance: when an organism becomes resistant to the highest clinically achievable dose of the antibiotic, i.e. it is no longer treatable with that antibiotic.
Resistance mechanisms fall into four main categories: 1. Modification of the target site 2. Metabolic bypass (reduced physiological importance of the target site) 3. Decreased drug accumulation in the bacterial cell 4. Antibiotic inactivation
1. Modification of target site • Occurs primarily through mutation. • Example: Streptomycin resistance in E.coli 1) Streptomycin inhibits protein synthesis by binding to the bacterial ribosome. 2) High level resistant E. coli have been found with a mutation at the Lys42 or Lys87 positions of the S12 ribosomal protein. 3) Mutations in rRNA genes have also been found to cause streptomycin resistance.
2. Metabolic bypass Reduces the importance of the antibiotic target site by providing an alternative pathway. Examples include: Methicillin resistance in staphylococci - due to the possession of an alternate penicillin binding protein (PBP2). Vancomycin resistance in enterococci - due to the possession of the vanA gene cluster which synthesises a modified pentapeptide building block for cell wall synthesis.
3. Decreased drug accumulation Can be achieved in one of two ways: 1. Prevent uptake of the drug by the cell 2. Active efflux of the drug from the cell Limited uptake • Responsible for a lot of intrinsic resistance, e.g. penicillins do not easily cross the outer membrane of Gram negative cells; Mycobacteria are impermeable to many drugs. • Alteration in outer membrane proteins can lead to low level resistance to several classes of drugs: • 1) Loss of D2 porin in Pseudomonas aeruginosa leads to imipenem resistance • 2) Altered porin expression in Salmonella has been associated with combined low level resistance to βlactams, aminoglycosides, chloramphenicol, tetracyclines, trimethoprim and quinolones.
Active efflux • The best studied example is tetracycline resistance – found in a wide range of both Gram positive and Gram negative bacteria. • It depends on the presence of an inner membrane protein (tet). This forms a multimer spanning the membrane and binds the drug in the presence of Mg2+, leading to its export from the cell in an energy dependent manner.
4. Antibiotic inactivation • This is the most commonly encountered mechanism of drug resistance. • Resistance can be achieved in one of two types of reaction: I. Hydrolysis of the antibiotic molecule e.g. β-lactamases II. Addition of groups to the antibiotic molecule e.g. chloramphenicol acetyl-transferase The genes for these enzymes are often associated with transposons and plasmids.
**REMEMBER TO STAY POSITIVE LIKE A PROTON!!**
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