Drug resistance

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(Redirected from
Resistance to antiviral drugs
)
An illustrative diagram explaining drug resistance.

Drug resistance is the reduction in effectiveness of a medication such as an

antineoplastic in treating a disease or condition.[1] The term is used in the context of resistance that pathogens or cancers 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
.

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][4]

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 neutralize it. Examples of target-altering pathogens are

enterococci and macrolide-resistant Streptococcus, while examples of antibiotic-modifying microbes are Pseudomonas aeruginosa and aminoglycoside-resistant Acinetobacter baumannii.[5]

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.[6] Some of the best alternative sources to reduce the chance of antibiotic resistance are probiotics, prebiotics, dietary fibers, enzymes, organic acids, phytogenics.[7][8]

Types

Drug, toxin, or chemical resistance is a consequence of

South East Asia and sub-Saharan Africa, and drug-resistant strains of Plasmodium falciparum are posing massive problems for health authorities.[12][13] Leprosy has shown an increasing resistance to dapsone
.

A rapid process of sharing resistance exists among

ecto-, plants, fungi, arthropods,[16][17] mammals,[18] birds,[19] reptiles,[20] fish, and amphibians.[20]

In the domestic environment, drug-resistant strains of organism may arise from seemingly safe activities such as the use of

sunblocks and any cosmetic or health-care product, insecticides, and dips.[26] The chemicals contained in these preparations, besides harming beneficial organisms, may intentionally or inadvertently target organisms that have the potential to develop resistance.[27]

Mechanisms

The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:[28][29]

  1. Drug inactivation or modification: e.g., enzymatic deactivation 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
    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
    efflux
    (pumping out) of the drugs across the cell surface.

Mechanisms of Acquired Drug Resistance

[30] [31]

Mechanism Antimicrobial Agent Drug Action Mechanism of Resistance
Destroy drug Aminoglycoside

Beta-lactam antibiotics (penicillin and cephalosporin)

Chloramphenicol

Binds to 30S Ribosome subunit, inhibiting protein synthesis

Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis

Bind to 50S ribosome subunit, inhibiting formation of peptide bonds

Plasmid encode enzymes that chemically alter the drug (e.g., by acetylation or phosphorylation), thereby inactivating it.

Plasmid encode beta-lactamase, which open the beta-lactam ring, inactivating it.

Plasmid encode an enzyme that acetylate the drug, thereby inactivating it.

Alters drug target Aminoglycosides

Beta-lactam antibiotics (penicillin and cephalosporin)

Erythromycin

Quinolones

Rifampin

Trimethoprim

Binds to 30S Ribosome subunit, inhibiting protein synthesis

Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis

Bind to 50S ribosome subunit, inhibiting protein synthesis

Binds to DNA topoisomerase, an enzyme essential for DNA synthesis

Binds to the RNA polymerase; inhibiting initiation of RNA synthesis

Inhibit the enzyme dihydrofolate reduces, blocking the folic acid pathway

Bacteria make an altered 30S ribosomes that does not bind to the drug.

Bacteria make an altered penicillin-binding proteins, that do not bind to the drug.

Bacteria make a form of 50S ribosome that does not binds to the drug.

Bacteria make an altered DNA topoisomerase that does not binds to the drug.

Bacteria make an altered polymerase that does not binds to the drug.

Bacteria make an altered enzyme that does not binds to the drug.

Inhibits drug entry or removes drug Penicillin

Erythromycin

Tetracycline

Binds to penicillin-binding proteins, Inhibiting peptidoglycan synthesis

Bind to 50S ribosome subunit, inhibiting protein synthesis

Binds to 30S Ribosome subunit, inhibiting protein synthesis by blocking tRNA

Bacteria change shape of the outer membrane porin proteins, preventing drug from entering cell.

New membrane transport system prevent drug from entering cell.

New membrane transport system pumps drug out of cell.

Metabolic cost

energy metabolism required to achieve a function.[32]

Drug resistance has a high metabolic price in pathogens[32] for which this concept is relevant (bacteria,[33] endoparasites, and tumor cells.) In viruses, an equivalent "cost" is genomic complexity. The high metabolic cost means that, in the absence of antibiotics, a resistant pathogen will have decreased evolutionary fitness as compared to susceptible pathogens.[34] This is one of the reasons drug resistance adaptations are rarely seen in environments where antibiotics are absent. However, in the presence of antibiotics, the survival advantage conferred off-sets the high metabolic cost and allows resistant strains to proliferate.[citation needed]

Treatment

In humans, the gene ABCB1 encodes MDR1(p-glycoprotein) which is a key transporter of medications on the cellular level. If MDR1 is overexpressed, drug resistance increases.[35] Therefore, ABCB1 levels can be monitored.[35] In patients with high levels of ABCB1 expression, the use of secondary treatments, like metformin, have been used in conjunction with the primary drug treatment with some success.[35]

For

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.[38][39] 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.[40]

Destruction of the resistant bacteria can also be achieved by phage therapy, in which a specific bacteriophage (virus that kills bacteria) is used.[41]

See also

References

  1. PMID 26180516
    .
  2. ^ "Antibiotic Resistance and Evolution". detectingdesign.com.[verification needed]
  3. ^ Harvey, Fiona (16 October 2016). "Use of strongest antibiotics rises to record levels on European farms". the Guardian. Retrieved 1 October 2018.[verification needed]
  4. ]
  5. ]
  6. ]
  7. .
  8. .
  9. ^ "Tolerance and Resistance to Drugs". Merck Manuals Consumer Version.
  10. ^ "Chemo 'Undermines Itself' Through Rogue Response",BBC News, 5 August 2012.
  11. S2CID 52092652
    .
  12. ^ McGrath, Matt (2012-04-05). "Resistance spread 'compromising' fight against malaria". BBC News.
  13. ^ Morelle R (20 October 2015). "Drug-resistant malaria can infect African mosquitoes". BBC News. Retrieved 21 October 2015.
  14. PMID 12849777
    .
  15. ^ "Mechanisms of drug action and resistance". tulane.edu.
  16. .
  17. ^ "Review Article on Colorado Potato Beetle Resistance to Insecticides". potatobeetle.org. Retrieved 1 October 2018.
  18. PMID 4540680
    .
  19. .
  20. ^ a b "Reptiles Magazine, your source for reptile and herp care, breeding, and enthusiast articles". reptilechannel.com. Archived from the original on 2011-01-03.
  21. ^ "How household bleach works to kill bacteria". physorg.com.
  22. ^ "Compete50 The complete mouth care products". Archived from the original on 2010-04-03. Retrieved 2010-07-18.
  23. ^ "The Dirt on Clean: Antibacterial Soap v Regular Soap". CBC News. Archived from the original on 6 August 2011.
  24. ^ "Should antibacterial soap be outlawed?". HowStuffWorks. 2007-11-07.
  25. S2CID 20734025
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  26. .
  27. ^ "Antibacterial cleaning products". Australian Department of Health & Human Services. Archived from the original on 4 March 2015. Retrieved 1 October 2018.
  28. PMID 19678712
    .
  29. .
  30. ^ Catherine A. Ingraham, John L. Ingraham (2000). Introduction to Microbiology second edition.
  31. ^ Catherine A. Ingraham, John L. Ingraham (2000). Introduction to Microbiology.
  32. ^
    PMID 9294886
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  33. .
  34. .
  35. ^ .
  36. .
  37. .
  38. .
  39. .
  40. .
  41. .

External links