Development of Antibiotics as a New Era in Disease Treatment - Essay Example

Development of antibiotics has opened a new era in disease treatment and understanding of the bacteria. During the next decade a host of prominent researchers systematically investigated the nature of bacteria and antibiotics, both its qualitative and its quantitative aspects. They found that antibiotics allow to neutralize or kill bacteria but ‘learn’ how to resist this impact. One important aspect of a scientific theory about a phenomenon is that it seeks to unravel and present in a clear way that phenomenon's causal properties and relations. "Virulence" and "pathogenicity" refer to the ability of bacteria to cause disease. “Bacteria are complex (while viruses must "live" in a "host" (us), bacteria can live independently) and so are easier to kill” (Antibiotics, Bacteria and (usually not) Viruses 2007). The traditional criteria for establishing that a bacterium is responsible for a disease have been Koch's postulates, which were developed in 1882. Although serving well for many years, these postulates have limitations: (1) not all bacteria can be cultured, (2) not all members of a species are equally virulent, and (3) adequate animal hosts are not always available. Host susceptibility is an important virulence factor for bacteria. The first important step in bacterial pathogenesis is adherence to a host cell. This occurs by means of pili, which consist of long rods that extend out from the bacterial surface. The tips of the pili contain proteins that attach to host cell receptors. In some cases, “pilin, the protein subunits of the pilus shaft, attach to the host cell's receptors. In addition to pili, bacterial surface proteins called adhesins attach firmly to the host cells” (Walsh 2003, p. 34). Sometimes the host makes antibodies against pili or adhesin proteins, and this induces the bacteria to make different types of adhesins. Only Gramnegative bacteria make adhesins; the mechanism of how Gram-positive bacteria attach to a host cell is not known (Walsh 2003). The virulence of many bacterial pathogens is due to the toxins they produce, which disrupt normal cell functions and cause cell death. Scholar and Pratt (2000) explain that “exotoxins are proteins that are excreted by dividing bacteria. Exotoxins that attack a variety of cell types are called cytotoxins” (p. 76); those that attack a particular cell type or tissue have specific names, such as neurotoxin, leukotoxin, hepatotoxin, or cardiotoxin. Exotoxins can be associated with a specific bacterial disease. In addition to toxic proteins, pathogenic bacteria also produce hydrolytic enzymes that degrade host tissues and disseminate bacteria within the host. Heat-shock proteins produced by bacteria stimulate autoimmune responses so that host antibodies and T-cells attack healthy host cells (Scholar and Pratt 2000). The essential property that differentiates antibiotics from antiseptics is that they are sufficiently selective to allow their use within the body, rather than just on the surface. This selective toxicity is not absolute but it is quantifiable as we shall see in chapter 6. There is, therefore, always room for improvements and developing drug licensing regulations seek improvements in the comparative safety of antibiotics. “Antibiotics work by destroying either the proteins that build a bacterium's cell wall or the protein-producing ribosomes” (Greene 2000, p. 23). The drug must inhibit the target bacteria at lower concentrations, usually much lower, than those concentrations that produce toxic effects in humans. Some antibiotics can be given in very high doses without toxic effects, e.g. penicillins, but others may produce serious toxicity at levels that are not much above those required for treatment of infection. Many alterations to antibiotics have been made to improve this selectivity; though with some antibiotics this is virtually impossible to achieve. The most selective antibiotics tend to be those that inhibit a process in bacteria that does not exist in mammalian cells, Antibiotics may or may not kill the bacteria. “If they do they are called bactericidal, if they merely inhibit replication of the bacteria which remain viable and may start to grow when the concentration of drug falls they are described as bacteriostatic” (Scholar and Pratt 2000, p. 45). The general perception both in the pharmaceutical industry and antibiotics that kill must be better than those that do not. Usually bactericidal drugs are to be preferred than bacteriostatic drugs, especially in “immuno-suppressed patients, but the over-riding consideration in assessing an antibiotic drug is experience of its efficacy in clinical practice” (Scholar and Pratt 2000, p. 112). An important factor in the cure of infection is the patient's own defense system; antibiotics cannot cure or prevent infection in the absence of adequate numbers of functional white cells in the blood. Antibiotics are well able to arrest the growth of the bacteria sufficiently for the patient's white cells to be able to eliminate the infection. The main impetus for altering the nucleus has been to overcome resistance. Antibiotics are conveniently classified, quite unjustifiably, into generations; in almost every case a new generation is introduced to overcome resistance to the previous generation. The basic nucleus is re-evaluated to add a functional chemical group so that the resistance mechanism which emerged to the original antibiotic cannot cope with the variant. The main types of antibiotics are β-lactams, penicillins, cephalosporins, etc. “Penicillins could penetrate the outer membrane of gram-negative bacteria so the half of the bacterial kingdom that were previously impervious to penicillins were now vulnerable” (Scholar and Pratt 2000, p. 43). Ampicillin was really remarkable when it was introduced in the 1960s, it covered infections caused by both gram-positive and gram-negativ bacteria. In fact it was to be preferred for some of the gram-positive infections, such as those caused by the Enterococcus or Listeria genus (Scholar and Pratt 2000). When Brotsu discovered the first cephalosporins 50 years ago, their initial advantage over the penicillins was considered to be that they had activity against gram-negative bacteria. In fact, it has turned out to be their remarkable ability to overcome antibiotic resistance mechanisms, particularly β-lactamases, that has proved to be their forte (Scholar and Pratt 2000). Carbapenems are natural β-lactams that rapidly penetrate gram-negative bacteria, these are the thienamycins (Walsh, 2003). Synthetic variants of these natural β-lactam compounds has resulted in the carbapenems.The nucleus of the carbapenems is similar to that of penicillins, with a five-membered side ring but differs in the replacement of sulphur by carbon. This is a difficult group of compounds to synthesise and they are inherently unstable. This makes them extremely expensive; however, like the fourth-generation cephalosporins, these are zwitterions and they have extremely rapid penetration into gram-negative bacteria. “So rapid and easy is their entry through the outer membrane that very few gram-negative bacteria are inherently resistant and the carbapenems have the broadest spectrum of activity of any of the β-lactam family” (Walsh 2003, p. 74). Antibiotic resistance is defined as the ability of bacteria to resist drugs. Antibiotics are unique amongst all pharmaceuticals in that they do not work forever. Bacteria somehow learn to adapt to survive in their presence. “Bacteria acquire resistance genes by any of three routes: inheritance, spontaneous mutations that produce new resistance traits, or acquisition of genes from other bacteria in their vicinity in a process known as "horizontal transfer" (Schmidt 2002, p. 396). This process requires mutation in the DNA of the bacteria and this takes not just time but also replication of the DNA. If a hefty, clinical dose of antibiotic is given, the speed of the antibiotic's attack is so fast that insufficient time is available for mutations or DNA replication. If the antibiotic is diluted or deficient, the drug trickles into the bacterium in insufficient concentrations to prevent either the cell dividing or DNA replication; a failure to inhibit the latter means that mutations can still occur and resistance emerges. This is the breeding ground of resistance because much antibiotic resistance comes from the use of too little antibiotic rather than too much (Greene, 2000. The mutation event is usually independent of the presence of the antibiotic and stems from random mutation events that occur in all genes during DNA replication. “Some of these changes happen because of chemical or radiation exposure; some just happen randomly, and no one's sure quite why” (Antibiotics, Bacteria and (usually not) Viruses 2007). Most mutations produce lethal consequences and the bacterial cell dies, but the bacteria are part of a large "family" so this wastage is unimportant. However, the mutation may produce a small change in a gene that does not result in lethality but rather gives the bacteria an advantage under certain environmental conditions. The most immediate of these would be if the bacteria were caught up surrounded by antibiotic. The antibiotic milieu selects those bacteria that have undergone a favourable mutation that enables them to proliferate; the bacteria that have not undergone mutation are inhibited by the antibiotic and will be unable to grow. “The single greatest factor driving resistance to a given antibiotic is simply use of the drug. The more an antibiotic is used, the more the bacteria become resistant to it” (Schmidt 2002, p. 396). The role of the antibiotic in resistance development is to select mutants that are produced spontaneously, regardless of the presence of the antibiotic; it does not induce the mutation itself. Almost everyone is aware that patients are urged to complete their course, even if the symptoms disappear. This precaution is merely to prevent the emergence of resistance, first for the patient's immediate relief so that a relapse does not occur with a resistant variant, which would then have to be treated with another antibiotic, and secondly to prevent resistant bacteria moving on to other patients (Greene, 2000; Drugs in Drinking Water 2002). Mutations that restrict entry and thus confer impermeability are often inefficient and do not provide significant levels of resistance. They may be manifested by alterations in the proteins that surround the porin channels. The porins are passages through the outer membrane of the cell; these pores allow polar or water-soluble nutrients into the cell and polar antibiotics exploit them to gain entry to the cell (Greene, 2000). Closing the pores makes the bacterium less permeable. Other antibiotics, such as tetracycline, are molecules that are so large that they have to use a transport system to carry them into the bacteria. Impermeability is manifested in mutations that disable the enzymes of this transport system. Impermeability is, however, not a common mechanism of resistance because besides its inherent incapability to confer high levels of resistance, it also usually confers an enormous burden on the cell. Restricted passage of antibiotics through the porins will also impede the passage of vital nutrients. Changes at specific amino acids, most usually at positions 83 and 87 in the α subunit, are associated with resistance; however, the levels of resistance that they confer are often very variable. Researcher (Walsh 2003) states that mutations can be associated with increases in MICs to only 0.5 mg per litre in Salmonella typhi but are associated with much higher levels of resistance in E. coli. Gram-positive bacteria are simpler than gram-negative and it assumed that they evolved first. It is known that the genes can readily transfer from gram-positive to gram-negative bacteria but not the other way round. According to Greene (2002): “Exciting developments in the new fields of cellular microbiology and microbial genomics are leading to a new understanding of infectious diseases, and there is good reason to believe that these studies will reveal a number of new targets for drug intervention” (p. 23). In sum, the information mentioned above demonstrate that microbiology is not dead knowledge or fixed knowledge. Antibiotics resistance creates new challenges for the scientists to create new effective drugs able to kill or neutralize bacteria and protect human body from illnesses. For one of the most important aims of this science is to generalize the existing knowledge and create new chemical substances. References 1. Antibiotics, Bacteria and (usually not) Viruses (2007). Retrieved 21 October 2007, from http://www.drreddy.com/antibx.html 2. Davies, J. (1999). Antibiotic Resistance: A Growing Health Threat. Forum for Applied Research and Public Policy 14 (1), 115. 3. Drugs in Drinking Water: Are Antibiotic-Resistant Superbugs Evolving? (2002). Journal of Environmental Health 64 (8), 50. 4. Greene, L.A. (2000). New Antibiotics Put Bacteria in a Bind. Environmental Health Perspectives 108 (12). 23. 5. Scholar, E.M., Pratt, W.B. (2000). The Antimicrobial Drugs. Oxford University Press, USA; 2 edition. 6. Schmidt, Ch. W. (2002). Antibiotic Resistance in Livestock: More at Stake Than Steak. Environmental Health Perspectives 110 (7), 396. 7. Walsh, Ch. (2003). Antibiotics: Actions, Origins, Resistance. ASM Press; 1 edition. Read More