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resistance Flashcards

1
Q

definition of resistance

A

insensitivity or decreased sensitivity to drugs that ordinarily cause inhibition of cell growth or cell death

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2
Q

intrinsic resistance

A

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.

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3
Q

acquired resistance

A

originally sensitive

undergo a change - this can happen when the patient is still recieving treatment

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4
Q

aminoglycoside resistance

A

TB
enterobacteriaceae - bacteremia, pneumonia, surgical wound infections
pseudomonas spp - bacteremia, pneumonia, UTI

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5
Q

Beta lactam resistance

A

enterobacteriaceae
neisseria gonorrhoea - gonorrhoea
haemophilus influenza - pneumonia, sinusitis, epiglottis, meningitis, ear infections

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6
Q

vancomycin

A

staphylococcus aureus - bacteremia, pneumonia, surgical wound infections
enterococcus spp. - catheter infections, blood poisoning

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7
Q

clindamycin

A

bacteroides spp - anaerobic infections, septicaemia

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8
Q

erythromycin

A

enterococcus sp - meningitis pneumoniae

streptococcus pneumoniae - meningitis, pneumonia

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9
Q

isoniazid, ethambutol, pyrazinamide, rifampicin

A

mycobacterium spp. - TB

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10
Q

chloramphenicol, ampicillin, trimethoprim, sulfamethoxazole, tetracycline

A

shigella dysentriae - severe diarrhoea

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11
Q

ciprofloxacin

A

pseudomonas aeruginoa - bacteremia, pneumoniae, UTIs

S. aureus - bacteremia, pneumonia, surgical wound infections,

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12
Q

chloroquine

A

plasmodium falciparum - malaria

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13
Q

selection

A

continuing antibiotic therapy preferentially eliminates drug sensitive cells. - selection pressure in favour of the resistant strain

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14
Q

classes of resistance mechanisms

A

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 )

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15
Q

beta lactam resistance

A

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 )
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16
Q

beta lactamases

A,B,C,D

A

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
17
Q

beta lactamases

A

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

18
Q

extended spectrum beta lactamases

A

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

19
Q

aminoglycoside resistance

A

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

20
Q

MRSA

mechanism of methicillin

mechanism of resistance

auxillary genes

A

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

21
Q

vancomycin resistance

patients at risk

clinical phenotype

A

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.

22
Q

macrolide resistance
erythromycin
expanded spectrum azithromycin clarithromycin

A

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

23
Q

combo resistance to sulfamethoxazole and trimethoprim

A

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.

24
Q

reduce uptake of drugs

A

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
25
Q

combo treatment for s aureus

A

beta lactam - affect cell wall synthesis so allow more entry of aminoglycosides by passive diffusion.

if drugs more hydrophobic - can only slow down entry - as cannot blck non protein mediated diffusion across cellular membranes.

alternatively active efflux in the cytoplasmic membrane.

26
Q

efflux

A

array of transporters with overlapping specificities
remarkable capacity to efflux drugs

either as intrinsically as chromosomally encoded metabolic capacity - such as in pseudomonas aeruginosa - making it intrinsically insensitive

or by acquisition of transport genes on plasmids and transposons.

beta lactam (G-)
chloramphenicol
tetracycline

27
Q

active efflux proteins

A

secondary active:

TetA ( h+ antiporter) g+, - ( tetracycline = specific efflux)

multidrug resistant pumps:

gram-ve:
AcrB -> Acr -> TolC
ie beta lactam - extruded from the periplasm
——————————————
primary active
ATP hydrolysis
PatAB

28
Q

multiple drug resistance

A

many antibiotic resistance mechanisms each specific for a class of drugs or one drug.

can be regulated by a master switch in same regulon
or co-localisation on the same resistance plasmid - R factor ( can be transferred by conjugation or transformation)

29
Q

multidrug resistance

A

multidrug efflux pump

30
Q

fluconazole

A

anti fungal
ergosterole synthesis
alteration in activity and amount of these enzymes
active azole efflux

31
Q

aciclovir

A

resistance of herpes to purine analogues

change in substrate specificity of viral thymidine kinase

32
Q

zidovudine

saquinavir

A

direct mutation that disable the interaction between drug and protein
zidovudine blocks RT
saquinavir blocks HIV protease

33
Q

chloroquine

A

exclusion of drug from the food vacuole by pump pfCRT.

give resistance against plasmodium

chemo (7 decks)

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