resistance Flashcards
definition of resistance
insensitivity or decreased sensitivity to drugs that ordinarily cause inhibition of cell growth or cell death
intrinsic resistance
inherent
eg lack of receptor
Polyene - requires presence of ergosterol - so bacteria are resistant to ergosterol
inadequate concentration at site of sensitive organisms- failure of funghi to respond to rifampicin ( cannot pass funghi wall) - resolved by simultaneous polyene
mycobacterium TB has intrinisc resistance to other drugs - due to high content of mycolic acid in complex lipid layer outside the PG layer - impermeable to many drugs
Isoniazid - inhibit biosynthesis of mycolic acid - first line against TB - but other bacteria which do not synthesis mycolic acid - resistant to it.
acquired resistance
originally sensitive
undergo a change - this can happen when the patient is still recieving treatment
aminoglycoside resistance
TB
enterobacteriaceae - bacteremia, pneumonia, surgical wound infections
pseudomonas spp - bacteremia, pneumonia, UTI
Beta lactam resistance
enterobacteriaceae
neisseria gonorrhoea - gonorrhoea
haemophilus influenza - pneumonia, sinusitis, epiglottis, meningitis, ear infections
vancomycin
staphylococcus aureus - bacteremia, pneumonia, surgical wound infections
enterococcus spp. - catheter infections, blood poisoning
clindamycin
bacteroides spp - anaerobic infections, septicaemia
erythromycin
enterococcus sp - meningitis pneumoniae
streptococcus pneumoniae - meningitis, pneumonia
isoniazid, ethambutol, pyrazinamide, rifampicin
mycobacterium spp. - TB
chloramphenicol, ampicillin, trimethoprim, sulfamethoxazole, tetracycline
shigella dysentriae - severe diarrhoea
ciprofloxacin
pseudomonas aeruginoa - bacteremia, pneumoniae, UTIs
S. aureus - bacteremia, pneumonia, surgical wound infections,
chloroquine
plasmodium falciparum - malaria
selection
continuing antibiotic therapy preferentially eliminates drug sensitive cells. - selection pressure in favour of the resistant strain
classes of resistance mechanisms
inactivation of drug
decreased uptake or increased efflux of drug
replacement amplification or modification of the drug
( target modification, enhanced DNA repair, metabolic bypass/ target replacement )
beta lactam resistance
beta lactamase
one strain of E.Coli - 10^5 beta lactamase molecules released per cell
single lactamase can hydrolyse 10^3 penicillin molecules per second
replacement of the drug target to eliminate or reduce binding of antibiotics
reduced uptake increased efflux ( AcrB--> Acr ---> Tol )
beta lactamases
A,B,C,D
A,C,D = serine enzymes - similar architecture and mechanistic to G transpeptidases - same type of penicilloyl O ser enzyme covalent intermediate - SAME EVOLUTIONARY ORIGIN
difference in outcome of reaction due to different half lives
A,C,D beta lactamase = millisecond range
transpeptidase - 90 minutes
water has free access to penicilloyl-O-Ser enzyme actve site so deacetylation is fast.
class B = zinc dependent no covalent penicilloyl enzyme intermediate uses zinc to directly activate water molecule and directly add to beta lactam ring cannot be inhibited by class A,C,D lactamase inhibitors
beta lactamases
E.Coli, Klebsiella pneumoniae + emergence in haemophilus influenza, neisseria gonorrhoea = led to development of EXTENDED SPECTRUM cephalosporins with oxyimino side chain , carbapenems, cephamycin, monobactam.
but led to emergence of extended spectrum beta lactamases ESBLs
extended spectrum beta lactamases
resistance to oxyimino - cephalosporins
some ESBLs such as CTX-M = from preexisting chromosomal ESBL gene from kluyvera spp - non pathogenic commensal organism
other ESBLs have point mutations - leading to single AA changes in existing class beta lactamases
sulbactam is beta lactamase inhibitor
aminoglycoside resistance
drug work by: read specific regions of 16s by hydrogen binding network through various amino and hydorxyl terminals on the cyclitol rings to provide a high affinity docking site for this class of drugs
strategy: covalently modify the specificity conferring OH and NH2 groups in the amino glycoside
1. N acetylation of nH2 by acetyl CoA
2. O-phosphoryl transfer of gamma phosphate of ATP to OH moiety
3. O - adenylyl transfer of alpha phosphate group of ATP - AMP transferred to OH of aminoglycoside
evolution: from N-acetyltransferases, phosphoryltransferases, adenyltransferases
similar acetyltransferases for streptogramin, chloramphenicol, others
MRSA
mechanism of methicillin
mechanism of resistance
auxillary genes
target replacement
methicillin = beta lactam antibiotic with bulky 2.6 dimethoxy-benzoyl substituent to circumvent beta lactamase activity ( enhance half life ie lifetime of the covalent penicillyol- O - lactamase acyl enzyme intermeidate
MRSA resistant to all beta lactam antibiotics and some non beta beta lactam ones too
90% of the time due to acquiring mecA gene - new beta lactam insensitive bifunctional transglycosylase/peptidase
= penicillin binding protein 2A
has interpeptide crossbridge between 3 lys and 4 d-ala
mix of l-gly, l-ser, l-ala
auxillary genes = fem gene( factor essential for expression of methicillin resistance) fem produces (gly)5 - better subtrate for mecA transpeptidase than the mixed interpeptide.
similar mechanism changing compo of transpeptidase or other penicillin binding proteins by streptococcus pneumoniae - community acquired pneumonia, meningitis, otitis media and sinusitis
vancomycin resistance
patients at risk
clinical phenotype
overuse of vancomycin as first line to methicillin resistance
enteroccocus = opportunistic in space vacated by other bacteria and immunocompromised individuals.
indwelling catheters, dialysis patients, undergoing cancer chemotherapy ( low wbc)
mostly enterococcus faecalis
major clinical phenotype = VanA followed by van B
differ by continuing sensitivity to glycopeptide teicoplanin
5 tendemly arranged genes found to be essential and sufficient for the 2 phenotyes
reprogramming the peptide terminus - Van H A X program the PG termini from n-acyl d- ala D -ala to N-acyl-dala-D- Lactate
the switch from D-ala to D -lactate gives a thousand times decrease in binding constant of vancomycin.
macrolide resistance
erythromycin
expanded spectrum azithromycin clarithromycin
pneumococci
in one study in south africa, 70% of MRSA also resistant to it.
mechanism: methylation of A2058 in 23rRNA of 50s subunit by RNA N methyltransferae
close to the macrolide binding site
also reduce affinit for lincosamides, streptotagmin B
without affecting rRNA function
combo resistance to sulfamethoxazole and trimethoprim
replace sensitive enzymes DHPS, DHFR by insensitive ones due to mutation in these genes = target modification
very high levels of exprsssion of sensitive DHPS ad DHFR - gives metabolic bypass
expression from high copy plasmids
genomic promotor up mutatios.
reduce uptake of drugs
aminoglyoside resistance ie in pseudomonas aeruginosa by reduced expression of the porin
modifty the membrane outer layer
after entering the periplasm, actively transported into the cytoplasm likely by oligopeptide transporters.
mutations in these transporters - reduce affinity for aminoglycoside or disable aminoglycoside transport all together
beta lactam (gram-ve) aminoglycoside
