Quinolones form a complex with DNA and DNA gyrase or Top IV (84). Quinolones inhibit the release of DNA from DNA gyrase, prevent
the rebinding of DNA strands, and break DNA (84, 85). As a rule of thumb, gram-negative bacterial activity correlates with
the inhibition of DNA gyrase, and gram-positive bacterial activity corresponds with the inhibition of Top IV.
Resistance to quinolones results from mutations in the genes' encoding for DNA gyrase and Top IV. Gene mutations change the
primary structure of DNA gyrase and Top IV. These small changes prevent the enzymes from binding to quinolones and forming
a quinolone–DNA–DNA gyrase (or Top IV) complex.
Inhibitors of bacterial-wall synthesis (β-lactam).
The β-lactam antibiotics are natural and semisynthetic compounds that inhibit several enzymes associated with the final
step of peptidoglycan synthesis and assembly. These antibiotics are derived from the β-lactam structure: a four-tiered ring
in which the β-lactam bond resembles a peptide bond. The β-lactam group includes the following five subgroups:
- Penicillins (e.g., 6-aminopenicillanic acid derivatives)
- Cephalosporins (e.g., 7-aminocephalosporanic acid derivatives)
- Cephalosporin-related agents (e.g., oxacephems and cephamycins)
- Carbapenems (e.g., imipenem)
- Monobactams (e.g., aztreonam) (86).
The β-lactam antibiotics inhibit bacterial-wall synthesis. The targets for β-lactam antibiotics are the penicillin-binding
proteins (PBPs), which are permanently inactivated. The PBPs have transpeptidase or carboxypeptidase activity that regulates
cell size and shape. In addition, PBPs are involved in cell division through the manufacture of new bacterial walls. Bacteria
have many PBPs, and each one has a separate function.
The following are the four major mechanisms of resistance to β-lactam antibiotics:
- Inactivation by β-lactamases
- Modification of target PBPs
- Efflux pumps
- Reduced OM permeability (86, 87).
Antimetabolites: inhibitors of folic-acid synthesis.
The specificity of these antibiotics stems from the fact that bacteria cannot use preformed folic acid and must synthesize
their own folic acid (88). Mammalian cells use folic acid from exogenous sources.
These antibiotics are analogues of paraaminobenzoic acid (PABA). Sulfonamides block bacterial reproduction by acting as competitive
inhibitors of PABA in the folic-acid metabolism cycle. The target molecule is dihydropteroate synthase (DHPS). Inhibition
of this enzyme results in the depletion of tetrahydrofolate (89). Therefore, sulfonamides are bacteriostatic. Sulfonamides
possess a broad range of activity against gram-positive and gram-negative bacteria. Sulfamethoxazole is the most popular drug
in this subgroup of antibiotics.
Resistance is common, and resistance to one sulfonamide provides resistance to all. Sulfamethoxazole resistance is the result
of either chromosomal mutations in the DHPS gene that yield drug-resistant forms of DHPS or efflux pumps (90–92).
Sulfanilamides. These antibiotics bind to dihydrofolate reductase (DHFR) and inhibit the formation of tetrahydrofolic acid. They are thus
bacteriostatic. Their spectrum of activity covers gram-positive and gram-negative bacteria. Trimethoprim (TMP) is representative
of this subgroup.
The major causes of TMP resistance are the following:
- Production of an altered DHFR that lacks the capacity to bind sulfanilamides
- Decrease in drug uptake
- Efflux pumps
- Overproduction of the normal DHFR (93–95).
Development of resistance to antibiotics
Resistance to antibiotics develops in only two major ways. The antibiotic, acting as a selective agent, can help propagate
resistance microorganisms. In other cases, particular genes provide resistance. If either of these two conditions is not present,
resistant bacteria are not developed.
Bacterial resistance to antibiotics is a natural outcome of selective pressure or evolution. Bacterialike organisms arose
more than three billion years ago and have been constantly faced with natural products that have antibacterial activity (i.e.,
antibiotics) and related organic molecules. Bacteria have acquired resistance genes to survive. When a random mutation provides
a bacterium with a resistance gene, its progeny will have a survival advantage and proliferate despite the presence of substances
that inhibit or kill competing microorganisms. Resistance genes are passed to other bacteria through various gene-transfer
processes. In general, bacterial resistance to antibiotics is either intrinsic (i.e., resulting from native genes) or acquired
(i.e., resulting from new genes).