Drug resistance

This article is about pathogen resistance to the effects of drugs. For human resistance to the effects of drugs, see Drug tolerance.

Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial, anthelmintic or an antineoplastic[1] in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used in the context of resistance that pathogens have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant. Even the immune system of an organism is in essence a drug delivery system, albeit endogenous, and faces the same arms race problems as external drug delivery.

The development of antibiotic resistance in particular stems from the drugs targeting only specific bacterial molecules (almost always proteins). Because the drug is so specific, any mutation in these molecules will interfere with or negate its destructive effect, resulting in antibiotic resistance.[2] Furthermore there is mounting concern over the abuse of antibiotics in the farming of livestock, which in the European Union alone accounts for three times the volume dispensed to humans – leading to development of super-resistant bacteria.[3]

Bacteria are capable of not only altering the enzyme targeted by antibiotics, but also by the use of enzymes to modify the antibiotic itself and thus neutralise it. Examples of target-altering pathogens are Staphylococcus aureus, vancomycin-resistant enterococci and macrolide-resistant Streptococcus, while examples of antibiotic-modifying microbes are Pseudomonas aeruginosa and aminoglycoside-resistant Acinetobacter baumannii.[4]

In short, the lack of concerted effort by governments and the pharmaceutical industry, together with the innate capacity of microbes to develop resistance at a rate that outpaces development of new drugs, suggests that existing strategies for developing viable, long-term anti-microbial therapies are ultimately doomed to failure. Without alternative strategies, the acquisition of drug resistance by pathogenic microorganisms looms as possibly one of the most significant public health threats facing humanity in the 21st century.[5]

Resistance to chemicals is only one aspect of the problem, another being resistance to physical factors such as temperature, pressure, sound, radiation and magnetism, and not discussed in this article, but found at Physical factors affecting microbial life.

Introduction

Drug, toxin, or chemical resistance is a consequence of evolution and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater fitness may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant. Unless the drug used makes sexual reproduction or cell-division or horizontal gene transfer impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in cancerous tumors where some cells may develop resistance to the drugs used in chemotherapy.[6] Chemotherapy causes fibroblasts near tumors to produce large amounts of the protein WNT16B. This protein stimulates the growth of cancer cells which are drug-resistant.[7] Malaria in 2012 has become a resurgent threat in South East Asia and sub-Saharan Africa, and drug-resistant strains of Plasmodium falciparum are posing massive problems for health authorities.[8][9] Leprosy has shown an increasing resistance to dapsone.

A rapid process of sharing resistance exists among single-celled organisms, and is termed horizontal gene transfer in which there is a direct exchange of genes, particularly in the biofilm state.[10] A similar asexual method is used by fungi and is called "parasexuality". Examples of drug-resistant strains are to be found in microorganisms[11] such as bacteria and viruses, parasites both endo- and ecto-, plants, fungi, arthropods,[12] mammals,[13] birds,[14] reptiles,[15] fish, and amphibians.[15]

In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of bleach,[16] tooth-brushing and mouthwashing,[17] the use of antibiotics, disinfectants and detergents, shampoos, and soaps, particularly antibacterial soaps,[18][19] hand-washing,[20] surface sprays, application of deodorants, sunblocks and any cosmetic or health-care product, insecticides, and dips.[21] The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.[22]

"Drug resistance develops naturally, but careless practices in drug supply and use are hastening it unnecessarily." - Center for Global Development

"The overuse of antibacterial cleaning products in the home may be producing strains of multi-antibiotic-resistant bacteria." - Better Health Channel - Australian Government

"The use and misuse of antimicrobials in human medicine and animal husbandry over the past 70 years has led to a relentless rise in the number and types of microorganisms resistant to these medicines - leading to death, increased suffering and disability, and higher healthcare costs." - World Health Organisation 2010

"Deaths from acute respiratory infections, diarrhoeal diseases, measles, AIDS, malaria, and tuberculosis account for more than 85% of the mortality from infection worldwide. Resistance to first-line drugs in most of the pathogens causing these diseases ranges from zero to almost 100%. In some instances resistance to second- and thirdline agents is seriously compromising treatment outcome. Added to this is the significant global burden of resistant, hospital-acquired infections, the emerging problems of antiviral resistance and the increasing problems of drug resistance in the neglected parasitic diseases of poor and marginalized populations." - WHO Global Strategy for Containment of Antimicrobial Resistance 2010

Mechanisms

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:

  1. Drug inactivation or modification: e.g., enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases.
  2. Alteration of target site: e.g., alteration of PBP — the binding target site of penicillins — in MRSA and other penicillin-resistant bacteria.
  3. Alteration of metabolic pathway: e.g., some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid.
  4. Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.[23]

Metabolic price

Biological cost or metabolic price is a measure of the increased energy metabolism required to achieve a function.

Drug resistance has a high metabolic price[24] in pathogens for which this concept is relevant (bacteria,[25] endoparasites, and tumor cells.) In viruses, an equivalent "cost" is genomic complexity.

Treatment

The chances of drug resistance can sometimes be minimized by using multiple drugs simultaneously. This works because individual mutations can be independent and may tackle only one drug at a time; if the individuals are still killed by the other drugs, then the mutations cannot persist. This was used successfully in tuberculosis. However, cross resistance where mutations confer resistance to two or more treatments can be problematic.

For antibiotic resistance, which represents a widespread problem nowadays, drugs designed to block the mechanisms of bacterial antibiotic resistance are used. For example, bacterial resistance against beta-lactam antibiotics (such as penicillins and cephalosporins) can be circumvented by using antibiotics such as nafcillin that are not susceptible to destruction by certain beta-lactamases (the group of enzymes responsible for breaking down beta-lactams).[26] Beta-lactam bacterial resistance can also be dealt with by administering beta-lactam antibiotics with drugs that block beta-lactamases such as clavulanic acid so that the antibiotics can work without getting destroyed by the bacteria first.[27] Recently, researchers have recognized the need for new drugs that inhibit bacterial efflux pumps, which cause resistance to multiple antibiotics such as beta-lactams, quinolones, chloramphenicol, and trimethoprim by sending molecules of those antibiotics out of the bacterial cell.[28][29] Sometimes a combination of different classes of antibiotics may be used synergistically; that is, they work together to effectively fight bacteria that may be resistant to one of the antibiotics alone.[30]

Destruction of the resistant bacteria can also be achieved by phage therapy, in which a specific bacteriophage (virus that kills bacteria) is used.

There is research being done using antimicrobial peptides. In the future, there is a possibility that they might replace novel antibiotics.

See also

References

  1. ↑ Drug Resistance at the US National Library of Medicine Medical Subject Headings (MeSH)
  2. ↑ "Antibiotic Resistance and Evolution". detectingdesign.com.
  3. ↑ https://www.theguardian.com/environment/2016/oct/17/use-of-strongest-antibiotics-rises-to-record-levels-on-european-farms?CMP=share_btn_fb
  4. ↑ Fisher, Jed F.; Mobashery, Shahriar (2010). "Enzymology of Bacterial Resistance". Comprehensive Natural Products II. Volume 8: Enzymes and Enzyme Mechanisms. Elsevier. pp. 443–201. doi:10.1016/B978-008045382-8.00161-1. ISBN 978-0-08-045382-8.
  5. ↑ "Reading: The Resistance Phenomenon in Microbes and Infectious Disease Vectors: Implications for Human Health and Strategies for Containment -- Workshop Summary - The National Academies Press". nap.edu.
  6. ↑ "Tolerance and Resistance to Drugs". Merck Manuals Consumer Version.
  7. ↑ "Chemo 'Undermines Itself' Through Rogue Response",BBC News, 5 August 2012.
  8. ↑ "Resistance spread 'compromising' fight against malaria". BBC News.
  9. ↑ Morelle, Rebecca (20 October 2015). "Drug-resistant malaria can infect African mosquitoes". BBC News. Retrieved 21 October 2015.
  10. ↑ Molin, S; Tolker-Nielsen, T (2003). "Gene transfer occurs with enhanced efficiency in biofilms and induces enhanced stabilisation of the biofilm structure". Current Opinion in Biotechnology. 14 (3): 255–61. doi:10.1016/S0958-1669(03)00036-3. PMID 12849777.
  11. ↑ "Mechanisms of drug action and resistance". tulane.edu.
  12. ↑ http://horizon.documentation.ird.fr/exl-doc/pleins_textes/pleins_textes_5/b_fdi_12-13/15697.pdf
  13. ↑ Lund, M. (1972). "Rodent Resistance to the Anticoagulant Rodenticides, with Particular Reference to Denmark". Bulletin of the World Health Organization. 47 (5): 611–8. PMC 2480843Freely accessible. PMID 4540680.
  14. ↑ Shefte, N.; Bruggers, R. L.; Schafer, E. W. (1982). "Repellency and Toxicity of Three Bird Control Chemicals to Four Species of African Grain-Eating Birds". Journal of Wildlife Management. 46 (2): 453–457. doi:10.2307/3808656. JSTOR 3808656.
  15. 1 2 "Reptiles Magazine, your source for reptile and herp care, breeding, and enthusiast articles". reptilechannel.com.
  16. ↑ "How household bleach works to kill bacteria". physorg.com.
  17. ↑ http://www.healthstores.com/dentists/new_dental_products.htm
  18. ↑ "The Dirt on Clean: Antibacterial Soap v Regular Soap". CBC News. Archived from the original on 6 August 2011.
  19. ↑ "Should antibacterial soap be outlawed?". HowStuffWorks.
  20. ↑ Weber, D. J.; Rutala, W. A. (2006). "Use of germicides in the home and the healthcare setting: Is there a relationship between germicide use and antibiotic resistance?". Infection Control and Hospital Epidemiology. 27 (10): 1107–1119. doi:10.1086/507964. PMID 17006819.
  21. ↑ Yoon, K. S.; Kwon, D. H.; Strycharz, J. P.; Hollingsworth, C. S.; Lee, S. H.; Clark, J. M. (2008). "Biochemical and Molecular Analysis of Deltamethrin Resistance in the Common Bed Bug (Hemiptera: Cimicidae)". Journal of Medical Entomology. 45 (6): 1092–1101. doi:10.1603/0022-2585(2008)45[1092:BAMAOD]2.0.CO;2. PMID 19058634.
  22. ↑ http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Antibacterial_cleaning_products
  23. ↑ Li, X, Nikadio H (2009). "Efflux-Mediated Drug Resistance in Bacteria: an Update". Drugs. 69 (12): 1555–623. doi:10.2165/11317030-000000000-00000. PMC 2847397Freely accessible. PMID 19678712.
  24. ↑ Gillespie, S. H.; McHugh, T. D. (1997). "The biological cost of antimicrobial resistance". Trends in Microbiology. 5 (9): 337–339. doi:10.1016/S0966-842X(97)01101-3. PMID 9294886.
  25. ↑ Wichelhaus TA, Böddinghaus B, Besier S, Schäfer V, Brade V, Ludwig A (2002). "Biological Cost of Rifampin Resistance from the Perspective of Staphylococcus aureus". Antimicrobial Agents and Chemotherapy. 46 (11): 3381–5. doi:10.1128/AAC.46.11.3381-3385.2002. PMC 128759Freely accessible. PMID 12384339.
  26. ↑ Barber, Mary; Waterworth, Pamela M. (Aug 8, 1964). "Penicillinase-resistant Penicillins and Cephalosporins". Br Med J. 2 (5405): 344–349. doi:10.1136/bmj.2.5405.344. PMC 1816326Freely accessible. PMID 14160224.
  27. ↑ Bush, K (Jan 1988). "Beta-lactamase inhibitors from laboratory to clinic". Clin Microbiol Rev. 1 (1): 109–123. PMC 358033Freely accessible. PMID 3060240.
  28. ↑ Webber, M.A.; Piddock, L.J.V. (2003). "The importance of efflux pumps in bacterial antibiotic resistance". J. Antimicrob. Chemother. 51 (1): 9–11. doi:10.1093/jac/dkg050. Retrieved 3 November 2014.
  29. ↑ Tegos, GP; Haynes, M; Strouse, JJ; Khan, MM; Bologa, CG; Oprea, TI; Sklar, LA (2011). "Microbial efflux pump inhibition: tactics and strategies". Curr Pharm Des. 17 (13): 1291–302. doi:10.2174/138161211795703726. PMID 21470111.
  30. ↑ Glew, Richard H.; Moellering, Jr., Robert C.; Wennersten, Christine (Jun 1975). "Comparative Synergistic Activity of Nafcillin, Oxacillin, and Methicillin in Combination with Gentamicin Against Enterococci". Antimicrob Agents Chemother. 7 (6): 828–832. doi:10.1128/aac.7.6.828. PMC 429234Freely accessible. PMID 1155924.

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