DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1376 penicillin that resistance developed quickly, terminating
the miracle. This serious development is ever present
with each new antimicrobial agent and threatens the
end of the antimicrobial era. Today, every major class of
antibiotic is associated with the emergence of significant
resistance. Two major factors are associated with
emergence of antibiotic resistance: evolution and clinical/
environmental practices. A species that is subjected to
pressure, chemical or otherwise, that threatens its
extinction often evolves mechanisms to survive under
that stress. Pathogens will evolve to develop resistance
to the chemical warfare to which we subject them. This
evolution is mostly aided by poor therapeutic practices
by healthcare workers, as well as indiscriminant use of
antibiotics for agricultural and animal husbandry purposes.
Poor clinical practices that fail to incorporate the
pharmacological properties of antimicrobials amplify
the speed of development of drug resistance.
Antimicrobial resistance can develop at any one
or more of steps in the processes by which a drug
reaches and combines with its target. Thus, resistance
development may develop due to:
• reduced entry of antibiotic into pathogen
• enhanced export of antibiotic by efflux pumps
• release of microbial enzymes that destroy the
antibiotic
• alteration of microbial proteins that transform
pro-drugs to the effective moieties
• alteration of target proteins
• development of alternative pathways to those inhibited
by the antibiotic
Mechanisms by which such resistance develops
can include acquisition of genetic elements that code
for the resistant mechanism, mutations that develop
under antibiotic pressure, or constitutive induction.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Resistance Due to Reduced Entry of Drug into Pathogen. The
outer membrane of gram-negative bacteria is a permeable barrier
that excludes large polar molecules from entering the cell. Small
polar molecules, including many antibiotics, enter the cell through
protein channels called porins. Absence of, mutation in, or loss of a
favored porin channel can slow the rate of drug entry into a cell or
prevent entry altogether, effectively reducing drug concentration at
the target site. If the target is intracellular and the drug requires active
transport across the cell membrane, a mutation or phenotypic change
that slows or abolishes this transport mechanism can confer resistance.
As an example, Trypanosoma brucei is treated with suramin
and pentamidine during early stages, but with melarsoprol and eflornithine
when CNS disease (sleeping sickness) is present.
Melarsoprol is actively taken up by trypanosome P2 protein transporter.
When the parasite either lacks the P2 transporter, or has a
mutant form, resistance to melarsoprol and cross resistance to pentamidine
occur due to reduced uptake (Ouellette, 2001).
Resistance Due to Drug Efflux. Microorganisms can overexpress
efflux pumps and then expel antibiotics to which the microbes would
otherwise be susceptible. There are five major systems of efflux
pumps that are relevant to antimicrobial agents:
• the multidrug and toxic compound extruder (MATE)
• the major facilitator superfamily (MFS) transporters
• the small multidrug resistance (SMR) system
• the resistance nodulation division (RND) exporters
• ATP binding cassette (ABC) transporters
Efflux pumps are a prominent mechanism of resistance for
parasites, bacteria, and fungi. One of the tragic consequences of
resistance emergence has been the development of drug resistance by
Plasmodium falciparum. Drug resistance to most antimalarial drugs,
specifically chloroquine, quinine, mefloquine, halofantrine, lumefantrine,
and the artemether-lumefantrine combination is mediated
by an ABC transporter encoded by Plasmodium falciparum multidrug
resistance gene 1 (Pfmdr1) (Happi et al., 2009). Point mutations
in the Pfmdr1 gene lead to drug resistance and failure of
chemotherapy. Drug efflux sometimes works in tandem with chromosomal
resistance, as is seen in Streptococcus pneumoniae, and
perhaps, Myobacterium tuberculosis. In these situations, induction of
efflux pumps occurs early, which increases the MIC only modestly.
However, this MIC increase is enough to allow further microbial
replication and an increased mutation frequency, which enable the
development of resistance via more robust chromosomal mutations
(Gumbo et al., 2007b; Jumbe et al., 2006).
Resistance Due to Destruction of Antibiotic. Drug inactivation is
a common mechanism of drug resistance. Bacterial resistance to
aminoglycosides and to β-lactam antibiotics usually is due to production
of an aminoglycoside-modifying enzyme or β-lactamase,
respectively.
Resistance Due to Reduced Affinity of Drug to Altered Target
Structure. A common consequence of either single point or multiple
point mutations is change in amino acid composition and conformation
of target protein. This change leads to a reduced affinity of
drug for its target, or of a prodrug for the enzyme that converts the
prodrug to active drug. Such alterations may be due to mutation of
the natural target (e.g., fluoroquinolone resistance), target modification
(e.g., ribosomal protection type of resistance to macrolides and
tetracyclines), or acquisition of a resistant form of the native, susceptible
target (e.g., staphylococcal methicillin resistance caused by production
of a low-affinity penicillin-binding protein) (Hooper, 2002;
Lim and Strynadka, 2002; Nakajima, 1999). Similarly, in HIV resistance
mutations associated with reduced affinity are encountered in
protease inhibitors, integrase inhibitors, fusion inhibitors, and nonnucleoside
reverse transcriptase inhibitors (Nijhuis et al., 2009).
Similarly, benzimidazoles are used against myriad worms and protozoa
and work by binding to the parasite’s tubulin; point mutations
in the β-tubulin gene lead to modification of the tubulin and drug
resistance (Ouellette, 2001).
Incorporation of Drug. An uncommon situation occurs when an
organism not only becomes resistant to an antimicrobial agent but
subsequently starts requiring it for growth. Enterococcus, which easily
develops vancomycin resistance, can, after prolonged exposure to
the antibiotic, develop vancomycin-requiring strains.