With great power comes great responsibility antibiotic resistance exemplifies this statement. Antibiotics are substances that kill or severely inhibit the growth of bacteria. Before antibiotics bacterial infections such as Tuberculosis were devastating (1). With the rise of antibiotic resistance there are fears of reverting back to the pre antibiotic era. This essay first looks at why antibiotic resistance arises, and the mechanisms pertaining to it. The latter part looks at methods of preventing and controlling resistance before it is too late and finally looking at drug options and hope for the future.
Antibiotics revolutionised medicine they are generally safe to use and a few pills can treat a potentially fatal infection. It has been said "Antibitoics are too good to be true, they are real miracle drugs" (2) Ironically there efficacy has led to their downfall and the rise of antibiotic resistance. Antibiotics target bacteria, they are living microrganisms, and they are not passive targets. Bacteria are subject to Darwinian natural selection, where by a small number of bacteria who have mutations leading to antibiotic resistance survive and there genes are then conserved after repeated treatment with antibiotics (3)
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This has been summed up in Levy's "Drug resistance equation fig1" (4) Both factors affect emergence of resistance in the absence of either factor drug resistance will not emerge.
Antibiotic +Resistance trait -ïƒ Antibiotic resitance problem
There are different types of antibiotic resistance- 1) restricted access to target ie an efflux pump that pumps antibiotics out of cytoplasm. 2) Inactivation of the antibody 3) Modification of the antibiotics target 4) failure to activate the antibody (5)
A summary of these mechanisms can be seen in fig2. Many mechanisms are not widely understood and bacteria may display multiple types of resistance mechanisms.
Fig 2 Showing common mechanism of antibiotic resistance (6)
Bacteria can become resistant by acquiring one or more of these mechanisms. This can occur from mutation however this comes with great risk as the mutation may compromise the bacterial cell. An easier way to acquire these resistant genes is from other bacteria (7). This can occur in a number of ways the best studied is conjugation which is akin to sexual reproduction, there is direct cell to cell transfer of DNA via plasmids through a protein complex. Fig 3 is a simple diagram showing the basic mechanism of conjugation. This is very worrying as resistance elements from one bacteria can be transferred to another species., For instance in the case of Bacteroides species in the small intestine before the 1970 they had a 25% resistance to tetracycline, and after the 1990s over 80% of the bacteroides were resistant to tetracycline, it appears this emerged due to gene transfer. (8) Plasmids can carry multiple resistance genes in a package and if just one of the genes provides an evolutionary advantage all the genes in the package will be conserved
Fig3 Diagram showing Conjugation (9)
One method to reduce the incidence of antibiotic resistance is to reduce use. This is not as simple as it sounds many factors are involved including education and polices targeted at clinicians and the general public. In Greece antibiotic over consumption was rife along with large amounts of resistant bacterial strains in hospitals in 1989 the problem was addressed in an audit. Restrictions polices were placed on antibiotics such as ceftazidime, education was given to clinicians about making an accurate diagnosis and in prescribing antibiotics, hygiene rules such as hand washing were implemented and a antimicrobial team was set up to organise the policies (10). There seemed to be a high levels of success there was a large reduction in use of restricted antibiotics and within 3 years resistance in pseudomonas aeruginosa fell from 45% to 8%. However this study did not show information on changes of the number of infections rendered untreatable by antibiotics. Greece like many other European countries law prohibits antibiotic sale over the counter but there is no way to detect and punish the practise (11). Which leads to increases in antibiotic resistance in the wider community as people may take them for viral infections such as the common cold. There is a need for greater education of the general through media and school curriculum to address these problems (12).
Addressing the issue at first seems simple take away the antibiotics and the resistance should diminish. It was assumed that antibiotic genes in the absence of antibiotic are less fit, and by natural selection the bacterial populations would revert back to antibiotic susceptible forms. However this is not always the case, it was shown over a period of 10 years a rapid return of resistance to gentamicin and tobramycin when gentamicin was reintroduced after amikacin use was discontinued in a hospital (13) as a result it is imperative that resistant bacterial levels aren't allowed to build up to high levels of resistance through prudent antibiotic use. (14). Having a resistance gene comes at a cost to the bacteria through increased energy expenditure and production of metabolites. The cost of resistance could be reduced allowing the bacterium to adapt to the resistance gene. Some resistance genes have negligible cost and it has been shown that a bleomycin resistance gene in Escherichia Coli give a survival advantage during prolonged starvation as the gene conferred protection against DNA damage which occurs during starvation (15)
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Traditional Antibiotics either kill or inhibit the growth of bacteria both methods are effective at dealing with infections, However they impose the pressures of natural selections so that the bacteria populations become resistant to them. The key to overcoming antibiotic resistance is avoiding the selection pressure. One method is targeting virulence factors. Virulence is the relative ability of the bacteria to cause disease for instance the production of toxins (16). Methods involve inhibiting production and expression of the toxin, or altering the toxins interaction with the host. In this way the bacteria will persist in the host but is effectively disarmed. Another method is targeting Quorum sensing which is akin to chemical signalling between bacteria cells involved in the formation of bio films (17). The host's defences can then clear up the bacteria. Potentially there will be reduced selection pressure as targeting virulence does not adversely affect the bacteria itself, however there is no clear virulence inhibiting pathway as of yet. Other novel antibiotic methods include inhibiting cell division, disrupting translation on ribosomes and drugs which work to prevent bacterial resistance mechanism working for instance inhibitors of B-lactamase( which break down B-lactam antibiotics such as penicillin) (18) .
The implications of antibiotic resistance are worrying. There is still hope for the future prudent use of antibiotics is the most practical way to slow or contain the emergence of resistance. This will require coordination of polices to encourage sustainable antibiotic use, and greater levels of awareness through education in the medical profession and general public. Ideas for new therapeutic options are encouraging however until such a time prudent antibiotic usage should be one of the main priorities.
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(1) A Rapid-Fire Weapon to Fight Tuberculosis, Scientific American November 1933 215;
(2) Levy SB. The Antibiotic Paradox: How Miracle Drugs Are Destroying the Miracle New York, Plenum, 1992.
(3) Anderson M. The pandemic of antibiotic resistance Nature Medicine 5. 1999 147 - 149
(4) Levy SB. Balancing the drug-resistance equation. Trends Microbiol. 1994 Oct;2(10):341-342.
(5)Salyers AA, Whit DD. Bacterial Pathogenesis: A Molecular Approach, 2nd ed. 560 pp. ASM Press, Washington, DC, 2001.
(6) Pratt CW, Cornely Essential Biochemistry John Wiley & Sons Inc 2010
(7) Salyers AA, Amabile-Cuevas CF. Why are antibiotic resistance genes so resistant to elimination? Antimicrob.Agents Chemother. 1997 Nov;41(11):2321-2325.
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(8) Shoemaker NB, Vlamakis H, Hayes K, Salyers AA. Evidence for extensive resistance gene transfer among Bacteroides spp. and among Bacteroides and other genera in the human colon. Appl.Environ.Microbiol. 2001 Feb;67(2):561-568.
(10) Giamarellou H, Antoniadou A. The effect of monitoring of antibiotic use on decreasing antibiotic resistance in the hospital. Ciba Found.Symp. 1997;207:76-86; discussion 86-92.
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(12) Azevedo MM, Pinheiro C, Yaphe J, Baltazar F. Portuguese students' knowledge of antibiotics: a cross-sectional study of secondary school and university students in Braga. BMC Public Health 2009 Sep 23;9:359.
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(15) Blot M, Hauer B, Monnet G. The Tn5 bleomycin resistance gene confers improved survival and growth advantage on Escherichia coli. Mol.Gen.Genet. 1994 Mar;242(5):595-601.
(16) Clatworthy AE, Pierson E, Hung DT. Targeting virulence: a new paradigm for antimicrobial therapy. Nat.Chem.Biol. 2007 Sep;3(9):541-548.
(17) Keller L, Surette MG. Communication in bacteria: an ecological and evolutionary perspective. Nat.Rev.Microbiol. 2006 Apr;4(4):249-258.
(18) Projan SJ. New (and not so new) antibacterial targets - from where and when will the novel drugs come? Curr.Opin.Pharmacol. 2002 Oct;2(5):513-522.