DRUG RESISTANCEBy Muhammed rashid ak Medical college calicut
Unresponsiveness of a microorganism to an antimicrobial. Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.
• It took less than 20 years for, bacteria to show signs of resistance.• Staphylococcus aureus, which causes blood poisoning and pneumonia, started to show resistance in the 1950s.• Today there are different strains of S. aureus resistant to every form of antibiotic in use.
Natural resistance- some microbes are always been resistant to certain AMA. They lack the metabolic process or the target site which is affected by the particular drug. Species or group charecteristics. Eg:gram negative bacilli are normally. unaffected by penicillin G,M.tuberculosis to tetracyclines. Does not pose clinical problem.
Acquired Resistance Development of resistance by an organism which was sensitive before ,due to the use of an AMA over a peried of time. This can happen with any organism and is a majour clinical problem. Devolopment of resistance is dependent on the microorganism as well as the drug. Eg: Staphylococci,coliforms,tubercle bacilli-rapid acquisition of resistance.
Mechanisms of drug resistance Drug inactivation or modification: e.g., enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of β-lactamases. Alteration of target site: e.g., alteration of PBP— the binding target site of penicillins — in MRSA and other penicillin-resistant bacteria. Alteration of metabolic pathway: e.g., some sulfonamide- resistant bacteria do not require (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.
• Reduced drug accumulation: By decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.
Antibiotics promote resistance• If a patient does not complete course of antibiotic Or forgets to take the doses regularly, then resistant strains get a chance to build up.• The antibiotics also kill innocent by standers bacteria which are non-pathogens. reduces the competition for the resistant pathogens.• The use of antibiotics also promotes antibiotic resistance in non-pathogens too.• These non-pathogens may later pass their resistance genes on to pathogens .
Resistance gets around• When antibiotics are used on a person, the numbers of antibiotic resistant bacteria increase in other members of the family.• In places where antibiotics are used extensively e.g. hospitals and farms antibiotic resistant strains increase in numbers
Resistant pathogensStaphylococcus aureus •Major resistant pathogen. •Found on the mucous membranes and the human skin of around a third of the population. extremely adaptable to antibiotic pressure. •Community-acquired MRSA responsible for rapidly progressive, fatal diseases, including necrotizing pneumonia, severe sepsis and necrotizing fasciitis. , •oxazolidinones, (oxazolidinone, linezolid),vancomycin are the antibiotics used.
Streptococcus and Enterococcus S. pneumonia is responsible for pneumonia, bacteremia, otitis media, meningitis, sinusitis, peritonitis and arthritis. Resistance of Streptococcus pneumoniae to penicillin and other beta-lactams is increasing worldwide.
Pseudomonas aeruginosaClostridium difficileSalmonella and e.coli
Resistance To β-lactam Antibiotics •Act by inhibiting the carboxy or transpeptidase or penicillin binding protiens in peptidoglaycon synthesis. •Resistance is caused by •β-lactamase(most common) •Mutation in the PBPs –reduced affinity •Reduced uptake and efflux.
β-lactamases •Catalyse the ring opening reaction of β-lactam moity. •Classified as classes A-D based on peptide sequence. •Class A,C,D have a serine at the active site. •Class B have four zinc atoms at their active site. So called-metallo β-lactamase. •Class A-active against benzyl pencillin. •Class B-effective against penicillins and cephalosporins. .
•Class C-Inducible,mutation lead to overexpression.•Class D-composed of OXA type enzymes whichcan hydrolyse oxacillin.β-lactamase InhibitorsClavunalic acid,sulbactamAltered PBP is responsible for resistance byStreptococcus pneumoniae(PBP1a,PBP2b,PBP2x).Haemophilus influenzae(PBP3A,PBP3b).
Resistance to Glycopeptide Antibiotic •Vancomycine and teicoplanin. •Bind the terminal D-alanine side chains of pepetidoglycan and prevent cross linking in gram positive bacteria. •Resistance to vancomycin is via a sensor histidine kinase(vanS) and a response regulator (vanR). •Van H encodes a D-lactate dehydrogenasealpha-keto acid redutase and generates D-lactate ,which is the substrate for VanA(D-Ala-D-Lac ligase). •Cell wall precurser terminate at D-Ala-D-Lac to which vancomycin bind with very low affinity. •This change in affinity is mediated by one Hydrogen bond. •Selective pressure.
Resistance to Aminoglycoside Antibiotics • Binding to the A site interferes with the accurate recognition of cognate t-RNA during translation and also perturb translocation of the t-RNA from the active A-site to the peptidyl t-Rna site(p-site). •High level resistance is due to methylation of r- RNA(not in previously susceptible). Mechanism in clinical aminoglycoside resistance is their structural modification by the enzymes in resistant organisms •Aminoglycoside phosphatase(APHs) •Aminoglycoside nucleotidyl transferase(ANTs) •Aminoglycoside acetyl transferase(AACs)
PreventionStructural modification.Eg:tobramycin-lacks 3’-OH group and is not a substrate for APH(3’)Amikacin-has an acylated N-1 group and is not a substrate.3’-oxo kanamycin
Resistance to Tetracycline Antibiotics •Resistant organisms are shigella flexneri,salmonella enterica,serovour typhimonium,MRSA,Streptococcus pneumoniae. •Majour mechanism of resistance are efflux and ribosomal protection. • Tet efflux protien exchange a proton for a tetracycline –Mg2+ complex reducing the intracellular drug concentration and protecting target ribosom.
Modifications 9-glycinyl tetracycline(9-glycylcyclines),9- amino acylamido derivative minocycline,N,N- dialkylamine or 9—t-butyl –glycylamido moity. Active against Tet gens.
Resistance to Flouroquinolone antibiotics•Flouroquinolone bind and inhibitDNA Gyrase(topoisomerase II)-DNA supercoilingTopoisomerase 4-strand separation during celldivision.•The A and B subunits of DNA gyrase are encodedby gyrA,gyrB ,•topoisomerase 4 encoded by ParC,parE.•Mutation to the gyrA ,involving substitution of aOH group with bulky hydrophobic group induceconformational change –flouroquinolone cantbind.
•Alteration involving ser80 and glut84 ofS.aureus grlA and seR79 ,Asp 83 ofs.pneumoniae par c led to quinoline resistance.•Changes in outer membrane permiability(nor Amediated efflux system ) –resistance in gram –ve.
Resistance to Macrolide ,lincosamide andstreptogramine•Inhibit bacterial protien synthesis by binding totarget site on mRNA.•Gram –ve- intrinsically resistant due topermiability barrier of the outer membrane.3 mechanisms of resistance in gram +ve.1.Target modification,involving adeninemethylation of domain-v of 23s ribosomal RNA.The adenine –N6- methyl transferase encodedby erm gene –resistance to erythromycine andother macrolide,lincosamide and group Bstreptogramins.
2.Efflux-Expression of mef gene-resistanes tomacrolide.Expression of msr-resistance to macrolide andstreptoganins. 3.Ribosomal mutation-in small no ofs.pneumoniae.
Resistance to Peptide Antibiotics-polymyxin Self promoted uptake across the cell envelop and perturb the cytoplasmic membrane barrier. Addition of a 4-amino-4-deoxy-L-arabinose(L- ara4N) moiety to the phosphate groups on the lipid A component of gram -ve bacteria leads to resistance.
Multiple drug resistance • A condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism. •Organisms that display multidrug resistance can be pathologic cells, including bacterial and neoplastic (tumor) cells.
Mechanisms in attaining multidrug resistance• No longer relying on a glycoprotein cell wall.• Enzymatic deactivation of antibiotics.• Decreased cell wall permeability to antibiotics• Altered target sites of antibiotic• Efflux mechanisms to remove antibiotics.• Increased mutation rate as a stress response.
R-FactorsIsolates become resistant to multiple ,chemicallydistinct agents in a single biological event.Eg:Previously sensitive E.coli become resistant tomultiple antibiotics through acqisition of aconjugative plasmid called R Factor from resistantsalmonella and shigella isolates.•Rp4-encoding resistance to ampicillin,kanamycin,tetracyclin and neomycin found inp.auriginosa and other gram –ves.•R1-encoding resistance to ampicillin,kanamycin,sulphonamides etc found in gram –ves•PsH6
Mobile gene cassettes and Integrons •Many gram –ve resistance genes are located in gene cassettes. •One or more of these cassettes are can be integrated in to a specific position on the chromosome termed as an integron. •Integrons are genetic element that recognises and capture multiple mobile gene cassettes. •4 types of integrons are identified.
Chromosomal multiple antibiotic resistance(Mar)locus•First described in e.coli.•Locus consists of two divergently transcribed units,mar c and marAB.•Increased expression of the marAB operon resultingfrom mutations in marO or marR,or frominactivation of marR following exposure to inducingagents such as salicylate leads to marR phenotype.•marR phenotype is characterised by resistance tostructuarally unrelated antibiotics,organicsolvents,oxidative stress and chemical disinfectants.
Neoplastic resistance Main cause of failure in treatment of cancer. Variety of factors like individual variation in patients and somatic cell genetic differences in tumour. Intrinsic or aquired. Reasons •Most common reason is expression of one or more energy dependent transporters that detects and ejects anticancer drugs from cells. •Insensitivity to drug induced apoptosis. •Induction of drug detoxifying mechanisms
Reference1.Text book of pharmaceutical biotechnology hugo @russels2.Pubmed
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