Mechanisms of resistanc

There are several genetic mechanisms by which resistance to antibiotics can develop in bacteria. These mechanisms give rise to resistance because they result in biochemical modifications that alter certain bacterial cell properties that normally render the cell sensitive to an antibiotic. Examples of biochemical modifications that lead to resistance include the production of enzymes that inactivate the drug; the alteration of the protein, enzyme, or receptor targeted by the drug; the activation of drug efflux pumps that deliberately remove the drug from the cell; and the alteration of cell-wall proteins that inhibit drug uptake.

There are two important types of genetic mechanisms that can give rise to antibiotic resistance: mutation and acquisition of new genetic material. In the case of mutation, the rate at which resistance develops can be attributed to the rate at which bacteria mutate. A mutation is a permanent change in an organism’s genetic material. Mutations occur naturally when cells divide. Bacteria are especially prone to mutation because their genome consists of a single chromosome and because they have a high rate of replication. The more replications a cell undergoes, the higher the chance it has to mutate. The acquisition of new genetic material also is a naturally occurring process in bacteria. This process appears to be the most common mechanism by which resistance develops; it is facilitated by the fact that bacteria are prokaryotic organisms (which means that they do not have a nucleus protecting the genome) and by the presence of small pieces of DNA called plasmids that exist in a bacterial cell separate from the chromosome. Thus, the genetic material of bacteria is free-floating within the cell, making it open to gene transfer (the movement of a segment of genetic material from one bacterial cell to another), which often involves the transmission of plasmids.

In nature, the primary mechanisms of bacterial gene transfer are transude and conjugation. Transduction occurs when a bacterial virus, called a bacteriophage, detaches from one bacterial cell, carrying with it some of that bacterium’s genome, and then infects another cell. When the bacteriophage inserts its genetic content into the genome of the next bacterium, the previous bacterium’s DNA also is incorporated into the genome. Conjugation occurs when two bacteria come into physical contact with each other and a plasmid, sometimes carrying a piece of the chromosomal DNA, is transferred from the donor cell to the recipient cell. Plasmids often carry genes encoding enzymes capable of inactivating certain antibiotics. The original source of the genes for these enzymes is not known with certainty; however, mobile genetic elements, called transposons (“jumping” genes), may have played a role in their appearance and may facilitate their transfer to other bacterial species. Because many of the plasmids carrying antibiotic-resistant genes can be transferred between different species of bacteria, widespread resistance to a specific antibiotic can develop rapidly.

The transmission of plasmids during conjugation has been associated with the generation of many different types of antibiotic-resistant bacteria. For example, conjugation involving a plasmid carrying the gene for resistance to methicillin (an antibiotic derived from penicillin) is suspected to have resulted in the generation of MRSA. Penicillin and methicillin work by weakening the wall of the bacterial cell; when the wall is compromised, the osmotic gradient between a bacterial cell’s cytoplasm and its environment forces the cell to lyse (break open). In MRSA the gene acquired through conjugation encodes a protein capable of inhibiting methicillin binding, preventing the drug from attaching to and disrupting its target protein in the bacterial cell wall. Another example is a plasmid carrying a gene that encodes the enzyme beta-lactamase. Beta-lactamase alters the structure of the penicillin molecule, rendering it inactive.

Transduction and conjugation result in a process called recombination. The new bacterial genomes that are produced from genetic recombination are called recombinants. Antibiotics do not create recombinants—antibiotic-resistant recombinants exist naturally by way of normal gene transfer events. However, antibiotics, and particularly the improper use of these drugs, provide selective pressure to bacterial colonies, whereby the most sensitive organisms are killed quickly, and the most resistant organisms are able to survive and replicate.

Prevention and drug development

The prospects of scientists developing new antibiotics as fast as bacteria develop resistance are poor. Therefore, other measures have been undertaken, including educating the public about the proper use of antibiotics and the importance of completing a full regimen as prescribed. Improvements in diagnostic equipment to facilitate the isolation and detection of resistant bacteria such as MRSA in hospital settings have enabled rapid identification of these organisms within hours rather than days or weeks. In addition, although efforts to fight bacteria by targeting them with bacteriophages were largely abandoned with the discovery of penicillin and broad-spectrum antibiotics in the 1940s, the growing presence of resistance has renewed interest in these methods. In addition, a significant amount of phage-therapy research was conducted throughout the 20th century in regions within the former Soviet Union. As a result, today in Georgia, which was once under Soviet rule, bandages saturated with bacteriophages against staphylococcus are commercially available as topical treatments for wounds and burns. In the 21st century, researchers worldwide were working to develop other topical and systemic phage therapies.