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Molecular mechanisms of resistance

The abilities of bacterial organisms to utilize the various strategies to resist antimicrobial compounds are all genetically encoded.

Intrinsic resistance is that type of resistance which is naturally coded and expressed by all (or almost all) strains of that particular bacterial species.  An example of instrinsic resistance is the natural resistance of anaerobes to aminoglycosides and Gram-negative bacteria against vancomycin. 

Changes in bacterial genome through mutation or horizontal gene acquisition,on the other hand, may consequently lead to a change in the nature of proteins expressed by the organism.  Such change may lead to an alteration in the structural and functional features of the bacteria involved, which may result in changes leading to resistance against a particular antibiotic. This is referred to as acquired resistance, which is limited to selected isolates of that particular species or group of microorganisms.

For example, we know that methicillin resistance of Staphylococcus aureus is primarily due to changes that occur in the penicillin binding protein (PBP), which is the protein which beta-lactam antibiotics bind and inactivate to consequently inhibit cell wall synthesis. This change is actually rendered by the expression of a certain mecA gene in some strains of these bacteria, which is hypothesized to have been induced by the excessive use of penicillin.  Expression of this mecA gene results in an alternative PBP (PBP2a) that has a low affinity for most ß-lactam antibiotics, thereby allowing these strains to replicate in the presence of methicillin and related antibiotics.

Some antimicrobial resistance is brought about by multiple changes in the bacterial genome. For example, Isoniazid resistance of Mycobacterium tuberculosis results from changes in the following genes: katG gene which encodes a catalase; inhA gene which is the target for isoniazid; the oxyR gene and neighboring aphC gene and their intergenic region.


Biological Versus Clinical Resistance

Biological resistance refers to changes that result in the organism being less susceptible to a particular antimicrobial agent than has been previously observed.  When antimicrobial susceptibility has been lost to such an extent that the drug is no longer effective for clinical use, the organism is then said to have achieved clinical resistance. It is important to note that often, biologic resistance and clinical resistance do not necessarily coincide.  From a clinical laboratory and public health perspective it is important to realize that biologic development of antimicrobial resistance is an ongoing process, while clinical resistance is dependent on current laboratory methods and established cut-offs.  Our inability to reliably detect all these processes with current laboratory procedures and criteria should not be perceived as evidence that they are not occurring.  (Forbes et al., 1998)



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