Antibiotics are made to inhibit the growth of bacterial populations by stopping or disabling integral functions of the cell. Many vital cell functions such as metabolic processes, biosynthetic pathways, energy transfer, motility, and the transport of substances are all dependent on enzymes. These proteins bind temporarily to one or more of the substrates of the reaction they catalyze. In doing so, they lower the amount of activation energy needed and thus speed up the reaction (Gale 25-26). Antibiotics often take advantage of this interplay between the enzymes and the dependent bacteria. Changing a single amino acid in an enzyme will cause variation in the target site (Neu 1065). Slight modification of the enzyme by the antibiotic may be enough to kill the entire cell.
Antibiotics disrupt various cell processes. Two antibiotic families, the penicillins and cephalosporins, prohibit the bacteria from making their protective cell walls. Three other families, the erythromycins, tetracyclines, and aminoglycosides all inhibit the bacteria from making the proteins necessary for their survival. Another group (trimethoprim and sulfamethoxazole) attacks the bacteria’s DNA replication machinery. Penicillin works by binding to, and inactivating, a protein that is crucial for cell wall synthesis (Smith 326). Penicillin inhibits the growth of the cell wall, but otherwise leaves the cell in tact (Gale 49). After subsequent growth, the bacteria will burst, resulting in lysis of the cell.
Resistance against penicillin achieved by changes in gene coding for these penicillin-binding-proteins (Smith 326). Gene changes result in modification of either the target site or the antibiotic itself. Alteration of penicillin involves one of three factors: (1) changing the target protein molecule so that the enzyme’s catalytic activities remain intact while the antibiotic’s interaction with the enzyme is lost, (2) a change in the “outer layers of the cell envelope” which prevents the penicillin from reaching the reaction sites, and (3) alteration of penicillin’s own enzyme used in cell wall lysis (Neu 1065).
The evolution (and resulting resistance) of bacteria is driven by genetic change. This change can be brought about horizontally by DNA originating outside of the organism or by a mutation of their own genome. Horizontal transfer is achieved by special DNA called plasmids and transposons. Plasmids are circular, double-stranded units of DNA that replicate within a cell independently of the chromosomal DNA. Transposons are also capable of independent replication. After they are replicated, the new segments of DNA can be inserted into a new position in the same chromosome, into a different chromosome, or in a plasmid. This creates an environment with high genetic interchange. In fact, several species of bacteria have evolved resistance to the spread of penicillin by obtaining plasmids that have gene that encodes for the enzyme β-lactamase (Smith 326). On the other hand, environments exist where genetic interchange is rare- either due to a lack of genetically compatible species or the inability of receptors to process the DNA. In this case, mutation of genes is the only solution (Blazquez 345).
Macroscopically, resistance is closely related to over-use of one certain class of antibiotics. In many cases, antibiotics are prescribed unnecessarily. With a recent trend of overly brief patient visits and heavy clinician workloads, overprescription has been a major contributor to this problem of increased resistance(Burke 1270). Viruses, which are not susceptible to antibiotics, account for a high percentage of our throat and respiratory infections. Unfortunately, while these antibiotics can be successful in killing off harmful bacteria strains, they can’t differentiate from harmless and harmful varieties (Novitt-Moreno 6). When a patient takes unnecessary antibiotics for their viral infection, the body’s harmless bacteria are introduced to the antibiotic and the chance of these bacteria developing resistance to the drug is increased (Novitt-Moreno 6). When the harmless bacteria evolve resistive mechanisms they are passed horizontally to harmful strains. Even if an antibiotic is properly prescribed and is effective in attacking susceptible bacteria, some resistant ones may survive, especially if not all of the medication is taken. These surviving resistant bacteria multiply as a resistant strain, and are more difficult to treat. The drug-resistant strains are likely to spread from one person to another (Novitt-Moreno 6).
People have suggested restricting access to antibiotics in order to slow the rate of adaptation. Controls on antibiotic distribution are even more relaxed in places other than the United States. Two years ago, on a trip to Cozumel, Mexico, my mom had some unknown tooth infection. After a simple trip to the local pharmacy (with no prescription), she came back with a bottle of penicillin. Handing out antibiotics without prescriptions only adds to the chance of microbial resistance. An obvious consensus has concluded that there is a need for practice guidelines and other institutional policies to control antibiotic usage. However, when faced with imminent needs of patients, doctors seem to lack commitment to this mission (Burke 1270). A large number of organizations and agencies have responded to this growing epidemic in the past few years, including the National Academy of Sciences, Institute of Medicine, the Infectious Disease Society of America, the Centers for Disease Control and Prevention, and the World Heath Organization (Burke 1). A commitment by these agencies to enforce regulations and guidelines on antibiotic use is a paramount step in solving this epidemic.
The inherent relationship between antibiotics and bacteria forces positive selection of bacteria containing a useful antibiotic resistive mechanism. Simply put, the bacteria that are incapable of resisting the antibiotics will be cleared from that population. This in turn increases the percentage of resistant bacteria in the population. Those successful bacteria will then reproduce and pass on their genes to new members of the pool, creating a chain reaction (Blazquez 347).
Antibiotics can also be indirect promoters of resistance. It has been measured by experimentation that populations of bacteria contain a 0.001% subpopulation of strong mutators. A single selection of a strong mutator by the antibiotic would increase the proportion of these rapid mutators from a dismal 0.001% up to a more reasonable 0.5%. As Mao et al speculate in the Blazquez text, “successive selections and the previous exposure to a mutagenic agent can increase the proportion of mutator strains up to 25% and 100% respectively in the selected population” (347). It would therefore follow that successive and prolonged antibiotic treatments increase the possibility of the microorganisms gaining new antibiotic resistance (Blazquez 347). The situation is more alarming in relation to cystic fibrosis. Up to 80% of cystic fibrosis patients are infected with Pseudomonas aeruginosa. After years of treatments, the P. aeruginosa inevitably becomes resistant to most of the antibiotics used in the treatments via horizontal transfer. It has been demonstrated by Blazquez et al “that up to 20% of the P. aeruginosa strains isolated from these patients are strong mutators and that there is a strong linkage between the mutator phenotype and its evolution to antibiotic resistance (347).” This data strongly suggests that antibiotic pressure is a main contributor in antibiotic resistance.
The situation seems paradoxical. If the antibiotics themselves augment the rate of mutation (which translates into resistance), then how can we ever solve the problem of antibiotic resistance? The answer lies in our development of new antibiotic molecules. An antibiotic’s capacity to produce resistance is a vital trait that must be studied when developing the drugs of the future. If this step is not taken, new bacterial strains will inevitably develop resistance to any drug we throw at them. The Blazquez paper suggests that developmental antibiotic molecules should be evaluated based on their tendencies for selecting “hypermutable variants, to increase mutation rates, and to promote genetic interchanges.” This molecule should be modified so that it reduces these destructive properties without compromising its antimicrobial properties (Blazquez 348). Therefore, by using our knowledge of how bacteria finds resistance, we can change our strategies for creating new antibiotics.
As bacteria continue to evolve resistance to more classes of antibiotics, drug companies are racing to produce new ones. Creating new drugs just creates more new diseases. Instead of combating and forcing old diseases into extinction, our inadvertent use of antibiotics is synthesizing more dangerous, resistive strains. Only appropriate use by patients, doctors, and drug companies will slow down and in many cases prevent emerging resistance.
Works Cited
Blazquez, et al. “Mutation and Evolution of Antibiotic
Resistance: Antibiotics as Promoters of Antibiotic
Resistance?” Current Drug Targets 3 (2002): 345-349.
Burke, John P. “Antibiotic Resistance-Squeezing the Balloon.”
The Journal of the American Medical Association 280.14
(1998):1270.
Gale, et al. The Molecular Basis of Antibiotic Action. New York:
Wiley, 1972.
Neu, Harold C. “The Crisis in Antibiotic Resistance.” Science
Aug. 1992: 1064-74.
Novitt, Anne. “Antibiotics: What’s Happening to our Miracle
Drugs?” Current Health 2 Dec. 1995: 6-13.
Smith, J. Maynard. “The Role of Evolution.” The Journal of
Heredity 84.5 (Sept-Oct 1993): 326-7.