Multi-drug resistance
All antimicrobials introduced
in the past 50 years have had resistance mechanisms specifically developed to
them by bacteria. The big picture does not look too good. Launched in the US in
Summer 2000, linezolid was the only class of new antibiotic that reached the
clinics in 35 years. However, resistance was reported within one year.
More we learn about
antimicrobial resistance, more we now realize that bacteria are much better
equipped than we thought in terms of dealing with challenges by all these
man-made bactericidal toxins including general-purpose disinfectants.
Four basic strategies
employed by bacteria to combat antimicrobials
[1] Alteration of the target site to avoid susceptibility
[2] Inactivation of the antimicrobial by enzymatic actions
[3] Metabolic pathway detour to avoid the antimicrobial effects
[4] Exclusion / extrusion of antimicrobial to maintain low
intracellular concentration
The
genetic determinants leading to resistance may come from mutation or
acquisition from other bacteria via horizontal gene transfer.
[1], [2] and [3] often
leads to cross resistance meaning the phenotypic changes resulted from the
genetic determinants confer resistance to more than one antibiotic from the
same class. For instances, Ser-83 mutation in the gyrase subunit A gene (gyrA)
causes increased resistance to nalidixic acids as well as other
fluoroquinolones such as ciprofloxacin in Shigella. Also the
metallo-beta-lactamase IMP-4 in acinetobacters confers increased resistance to
imipenem as well as meropenem (Chu et al., 2001).
On the other hand, [4]
often leads to resistance to structurally unrelated compounds i.e. resistance
to more than one class of antimicrobials (multi-drug resistance). Also, it may
be an active or passive process. For instances, utilizing cellular energy, the
AdeABC efflux pump in Acinetobacter baumannii confers increased
resistance to chloramphenicol, tetracycline, aminoglycosides and
fluoroquinolones. Reducing membrane permeability by altering the number and/or
structure of membrane porins such as OmpF in Escherichia coli can
result in exclusion of cationic surfactants and several beta-lactams and
therefore low-level multi-drug resistance.
MDR could also arise from
linkage between several resistance genes. If these linked genes manage to
hitchhike genetic elements such as transposons and plasmids, they could jump
from bacterium to bacterium. Integron, a specialized class of genetic element
with a built-in promoter is capable recruiting and expressing genes, a true
natural bacterial genetic engineering apparatus. Although integron is not
capable of self-transposition, it can assemble batteries of adaptive genes and
allow them to be mobilized by transposons and insertion sequences. Therefore,
integrons can be viewed as MDR determinants that can be disseminated.
References
Chu et al., 2001 Antimicrob. Agents Chemother. 45:710-4. PubMed
Magnet et al., 2001 Antimicrob. Agents Chemother. 45:3375-80. PubMed
Useful links:
http://www.foodsafetynetwork.ca/animal/ab-res-ppr-wjp.htm
http://www.bentham.org/ctmc1-1/poole/keithpoole.htm
http://www.sci.sdsu.edu/~smaloy/MicrobialGenetics/topics/topics-detail.html
Interesting articles:
Hawkey, 1998 BMJ
317:657-60. Full text
http://www.nature.com/nsu/010308/010308-3.html
http://www.nature.com/nature/links/020613/020613-3.html
http://www.cdc.gov/ncidod/eid/vol7no3/carattoli.htm