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Resistance occurs when a previously susceptible organism is no longer
inhibited by an antibiotic at a concentration that can be safely
achieved in clinical practice. Resistance can develop quickly because:
- bacteria multiply rapidly;
- mutations arise regularly;
- segments of DNA can transfer by transformation;
- genes can be transferred rapidly by bacteriophages, plasmids or
other mobile genetic elements.
Antibiotic use favours the survival of resistant organisms. The
replication of organisms that have accidentally developed mechanisms
to avoid destruction can pose a threat to the successful
treatment of infections.
Transmission of resistance determinants between bacteria
Many bacterial species incorporate naked DNA into their genome,
a process called transformation. For example, Streptococcus pneumoniae
and Neisseria gonorrhoeae incorporate small sections of
penicillin-binding protein genes from closely related species to
produce a penicillin-binding protein that binds penicillin less
avidly, so becoming more resistant. Such organisms are still able
to synthesize peptidoglycan and maintain their cell walls in the
presence of penicillin.
Bacteria contain plasmids, circular DNA structures that are found
in the cytoplasm. Many genes are carried on plasmids including
those that encode metabolic enzymes, virulence determinants and
antibiotic resistance. Plasmids can pass from one bacterium to
another by conjugation allowing 'resistance genes' to spread
rapidly in populations of bacterial species that share the same
environment (e.g. within the intestine). Combined with antibiotic
selective pressures (e.g. in hospitals) that favour the survival of
organisms with resistance plasmids, multiresistant populations
Transposons and integrons
Transposons and integrons are mobile genetic elements able to
encode transposition and move between the chromosome and
plasmids, and between bacteria. Many functions, including antibiotic
resistance, can be encoded on a transposon. Resistance to
methicillin among Staphylococcus aureus and to tetracycline
among N. gonorrhoeae probably entered the species by this route.
Integrons are important in transmission of multiple drug resistance
in Gram-negative pathogens. Resistance genes can also be
mobilized by bacteriophages (viruses that live in bacteria).
Multiple resistance can develop on mobile genetic elements because
once a gene is established on the element, it can readily acquire
resistance to another agent by one of the mechanisms above. Once
there is more than one resistance gene, exposure to any of these
agents will permit survival of the organism, which increases the
risk of further resistance being acquired.
Mechanisms of resistance
A common resistance mechanism is degradation of the antibiotic.
Many strains of S. aureus produce an extracellular enzyme (β-
lactamase), which can break open the penicillin β-lactam ring,
thereby inactivating it. In the face of newer β-lactam antibiotics,
many human pathogens have acquired a range of genes that
encode broad-spectrum β-lactamases; these include Escherichia
coli, Haemophilus influenzae and Pseudomonas spp. The genes are
often found on mobile genetic elements (transposons). The spread
of different types of extended-spectrum β-lactamases (ESBLs),
such as CTX-M and AmpC, among Enterobacteriaceae is producing
resistance to cephalosporins and broad-spectrum penicillins in
organisms that cause hospital-associated infections. Spread to the
community has already occurred.
Some bacteria express enzymes that add an inactivating chemical
group to the antibiotic, so inhibiting its activity. Bacteria may
become resistant to aminoglycosides by adding an acetyl, amino
or adenosine group to the antibiotic molecule. Different aminoglycosides
differ in their susceptibility to this modification, amikacin
being the least susceptible. Aminoglycoside-resistance enzymes are
found in Gram-positive organisms (e.g. S. aureus) and Gramnegative
organisms (e.g. Pseudomonas spp).
Some bacteria are naturally resistant to antibiotics because their
cell envelope is impermeable to that particular antibiotic (e.g.
Pseudomonas spp. are impermeable to some β-lactam antibiotics).
Aminoglycosides enter bacteria by an oxygen-dependent transport
mechanism and so have little effect against anaerobic organisms.
Other bacteria may lose a porin protein, so creating a permeability
barrier that stops antibiotics from entering the cell.
Bacteria, for example E. coli
or streptococci, may become resistant
to tetracyclines, macrolides or fluoroquinolones by the acquisition
of an inner membrane protein that actively pumps the antibiotic
out of the cell - an efflux pump.
Bacteria may acquire genes that create an alternative pathway that
can circumvent the metabolic block imposed by an antibiotic. S.
aureus becomes resistant to methicillin or flucloxacillin when it
acquires the gene mecA, which encodes an alternative penicillinbinding
protein (PBP2') that is not inhibited by methicillin.
Although the composition of its cell wall is altered, the organism
is still able to multiply.
Alteration of the target site
Rifampicin acts by inhibiting the β-subunit of RNA polymerase.
Resistance develops when the RNA polymerase gene is altered by
point mutations, insertions or deletions. The new RNA polymerase
is not as easily inhibited by rifampicin and resistance occurs.
Similarly, an alteration of the binding sites on DNA gyrase (the
target of fluoroquinolones) can make an organism resistant.
The genes responsible for these effects are often found in a small
region of the target gene, for example in the rifampicin resistancedetermining