Drugs for Defense and Drug Resistance
Antibiotics
Penicillin
Bacterial infections like tuberculosis, syphilis, and salmonella are treated with antibiotics. The term antibiotic originates from the Greek term anti meaning against, and bio meaning life. The history of modern antibiotics began with the discovery penicillin from the Penicillium mold by Sir Alexander Fleming in 1928. 32 During his work with Staphylococcus, Fleming found that his culture plate had patches that were bacteria-free: he discovered that these patches were produced by a mold, which fell on the plates and produced a substance that killed bacteria. 33 The reason why penicillin was an effective antibiotic is because penicillin disrupts the synthesis of the peptidoglycan cell wall of bacteria. It does this by preventing cross-linkages from binding to the long chains of peptidoglycan, causing the molecules to be unlinked and unable to synthesis a rigid cell wall. Unfortunately, today there are certain bacteria that are resistant to penicillin thus scientist have had to create other drugs that similar but different enough from penicillin to combat bacteria that have become resistant. Methicillin is an example of this.
Methicillin
By 1953, the wide use of penicillin led to development of S. aureus organisms that were resistant to penicillin. Staph infections steadily rose in hospitals despite efforts to create modified penicillin antibiotics to combat the new strains. One example of this new antibiotic was methicillin. Methicillin was initially effective because it was able to prevent S. aureus from producing beta-lactamase, the enzyme responsible for penicillin resistance. The problem stems from genetic alterations and auxiliary gene expression that ultimately disrupts the drug's main function. 34 However, just like penicillin within the first decade of its use, resistance against methicillin began to sprout. By 2005, 55% of ICU and 59.2% of non-ICU patients showed signs of MRSA. 35 Today, 95% of patients with S. aureus infections show signs of multi-drug resistance. Thus, health care professionals are forced to prescribe numerous antibiotics, increase dosages in order to treat infections that once were cleared away by one drug.
Natural antibiotics like penicillin, actinomycetes, and bacillus are found in soil and are designed to destroy surrounding organisms that may make survival more difficult, i.e. competition for space or food sources. Modern antibiotics are highly specific for the bacteria they are to affect. The antibiotic may be designed to inhibit the bacteria's ability to enter a host cell, disrupt the bacteria's energy source, create a cell wall, modify transcription, and change ribosome function and the synthesis of proteins, thereby preventing bacterial reproduction. 36 37 In the end, all antibiotics function to either kill or inhibit its target bacterium.
Antibiotic Resistance
How exactly do bacteria become resistant? One way is for the bacteria to use enzymes like beta-lactamase to destroy the antibiotic's chemical make-up. B-lactamase is an enzyme that is produced by bacteria. Antibiotics, like penicillin become ineffective if the bacteria are producing beta-lactamase to protect its cell wall because the enzyme attacks the B-lactam ring on the antibiotic. 38 Second, bacteria can develop methods to prevent the insertion of antibiotic into itself. Third, the receptor-protein targets can change causing the antibiotic to no longer recognize its molecular target. Because of the wide-use, misuse, and abuse of antibiotics and antiviral drugs by clinicians and their patients, targeted bacteria and viruses have adapted and evolved to too many drugs that were once affective in their eradication. As a result, scientists struggle to keep up with the rate of antimicrobial resistance to produce drugs that are affective against new or more evolved strains of the microbes.
Antiviral Drugs
Antiviral drugs like antibiotics are designed to inhibit a virus from replicating and infecting other cells. Scientists seeking to cure people of their infection look for weaknesses in the virus to create antiviral drugs. Drugs like Tamiflu and AZT (zidovudine) disrupts a virus's ability to replicate. 39
Tamiflu
The pharmaceutical giant Roche successfully marketed a neuraminidase inhibitor to combat multiple strains of the influenza virus. Tamiflu (osteltamivir) is an effective oral antiviral drug if taken within the first 48 hours of infection. It works by binding to the neuraminidase active site and thereby competing for the enzyme's substrate. Later, during protein synthesis inside the host cell, Tamiflu binds to neuramidase proteins, preventing them from reassembling to create a new virion. 40 Because Tamiflu can affect both A and B strains of the influenza virus and disrupt the virus's replication mechanism later in its life cycle, the drug is more than likely to not develop drug resistance strains. Currently, 33 million patients have been treated with Tamiflu worldwide. Studies show that the drug is effective in reducing influenza's symptoms. Furthermore, Japanese studies on the development of resistance to the drug shows that there is a low frequency of resistance among the 1180 influenza patients used in the study. 41
AZT & AZT resistance
AZT (zidovudine) was the first approved treatment for HIV infected persons. AZT is an antiretroviral drug which has promising affects on HIV disease. Patients using AZT have prolonged lives due to its ability to reduce opportunistic infections, prevent deterioration of the body, increase T-lymphocyte counts, and decrease mortality. Among asymptomatic HIV infected persons, AZT seems to delay the virus's progression. It is given to HIV infected mothers to prevent transmitting the virus to their baby. As an antiviral drug, AZT falls under the category of reverse-transcriptase inhibitor: AZT selectively inhibits the viral protein reverse transcriptase, preventing the virus from making a DNA copy of its genome and, therefore, preventing the virus from inserting its genes into the host genome. In higher doses it may also inhibit the function of DNA polymerase, a key enzyme in DNA replication. Despite AZT's effectiveness against the HIV virus, resistance to the anti-retroviral drug has developed. With use and time, HIV's reverse transcriptase becomes less and less susceptible to the inhibitor, thus decreasing AZT's efficacy.
Vaccines
Unlike antibiotics and antiviral medications, vaccines make use of the immune system's natural processes to fight disease. Once a person has been exposed to a microbe, a normal immune system will produce antibodies to recognize future exposure to the microbial pathogen. When the microbe is seen for the second time, antigens are recognized by the immune system rapidly and more aggressively, owing to the previous experience of the immune system and the production of more copies of the antibody.
The term vaccine came from Edward Jenner who serendipitously discovered a milkmaid's immunity against smallpox because of their exposure to cowpox. Jenner coined the term vaccine from the Latin word vac- meaning cow. Later, Louis Pasteur, developed vaccines against rabies, and by the 1950s and early 60s vaccines for polio, measles, and rubella were readily available. Vaccines require scientists to isolate either a live virus, a dead virus, or a genetically engineered virus: in the application of a vaccine, a healthy human is exposed to its weakened or less virulent form. In doing so, the body's immune system creates antibodies and vaccine-activated T cells, which can prevent disease upon future exposure to the more virulent strain.
Disinfectants
The practice of disinfecting household and hospital surfaces could potentially lead to bacteria that are both resistant to disinfectants and antibiotics. Doctors and researchers are worried that the increased use and misuse of disinfectants are selectively allowing for the evolution of bacterial strains. Thus, the defense lines that hospitals have in place to reduce infection are threatened. Furthermore, using biocides (chemicals used to kill bacteria), appear to help in the mutation of Staphylococcus aureus, such that S. aureus developed protein pumps that allowed it to produce an anti-antibiotic chemical. Fortunately, scientists are developing chemicals that may disrupt the protein pumps from producing their anti-antibiotic product. Researchers in Tel Aviv have found the enzyme causing the antibiotic against S. aureus to become ineffective. In finding the enzyme, they were able to use it against the bacteria by integrating it into antibiotics, thus improving the efficacy of the antibiotic against S. aureus. 42 The message is clear, misuse or antimicrobial products, not finishing an antibiotic/antiviral regimen, overdosing, and overuse can lead to more resistant strains of bacterial and viral strains. Over time, what are scientist and health care professionals going to do with strains of infectious diseases they do not have the power to treat?
Comments: