Mechanisms Of Resistance
Antibiotics, whether made in the laboratory or in nature by other microbes, are designed to hinder metabolic processes such as cell wall synthesis, protein synthesis, or transcription, among others. If humans are to prosper against microbial disease, it is necessary to understand how and why bacteria are able to mount their clever defenses. Aided with the knowledge of the genetics and mechanisms of resistance, scientists can discover new ways to combat the resistant bacteria.
The phenomenon of antibiotic resistance in some cases is innate to the microbe. For instance, penicillin directly interferes with the synthesis of bacterial cell walls. Therefore, it is useless against many other microbes such as fungi, viruses, wall-less bacteria like Mycoplasma (which causes "walking pneumonia"), and even many Gram negative bacteria whose outer membrane prevents penicillin from penetrating them. Other bacteria change their "genetic programs," which allows them to circumvent the antibiotic effect. These changes in the genetic programs can be in the form of chromosomal mutations, acquisition of R (resistance) plasmids, or through transposition of "pathogenicity islands."
An example of a chromosomal mutation is the increasing number of cases of penicillin-resistant Neisseria gonorrhae. This bacterium mutated the gene coding for a porin protein in its outer membrane, thereby halting the transport of penicillin into the cell. This is also termed "vertical evolution," meaning that the spread occurs through bacterial population growth. The most common method by which antibiotic resistance is acquired is through the conjugation transfer of R plasmids, also termed "horizontal evolution." In this method the bacteria need not multiply to spread their plasmid. Instead the plasmid is moved during conjugation. These plasmids often code for resistance to several antibiotics at once.
The third method is transfer due to transposable elements on either side of a "pathogenicity island," which is group of genes that appear on the DNA and carry the codes for several factors which make the infection more successful. These transposable elements allow the genes to jump from bacteria to bacteria or simply from chromosome to plasmid within the organism.
The "road blocks" that bacteria have evolved which result in antibiotic resistance employ several mechanisms. One strategy is simply to destroy or limit the activity of the antibiotic. The beta-lactamases are enzymes which render the penicillin-like antibiotics dysfunctional by cleaving a vital part of the molecule. Some bacteria can deactivate antibiotics by adding chemical groups to them; for instance, by changing the electrical charge of the antibiotic through the addition of a phosphate group. Other bacteria accomplish a similar effect by bulking themselves up with the addition of an acetyl group.
Still other bacteria acquire resistance by simply not allowing the antibiotic to enter the cell. The bacterium mentioned above, Neisseria gonorrhea, has altered porin proteins, thereby stopping uptake of the antibiotic. Some bacteria acquire intricate pumping mechanisms to expel the drug when it gains entry to their cell.
Finally, bacteria may mutate the gene for the target macromolecule with which the antibiotic is supposed to bind. For example, tetracycline binds to and inhibits ribosomes, so a mutation in the ribosomal genes may cause conformational alterations in the ribosomal proteins that prevent tetracycline from binding but still allow the ribosome to function.