resistance - Global Perspective Flashcards
what kind of resistance, would be called an “intrinsic resistance” with a bacterial species.
but what is at least one advantage of this type of resistance.
- impermeability
- absence/changes in drug target
> this type of resistance is somwhat predictable.
what type of drugs are anaerobic bacteria naturally resistant to, and why?
aminoglycosides - because they lack the oxidative metabolism to drive uptake of aminoglycosides.
what drugs are aerobic bacteria naturally resistant to, and why?
metranidozol - inability to anaerobically reduce drug to active form.
What drug are gram positive bacteria naturally resistant to, and why?
Aztreonam (β-lactam) Lack of penicillin binding proteins (PBPs) that bind and are inhibited by this beta lactam antibiotic.
What drugs are gam negative bacteria naturally immune to, and why?
Vancomycin, lack of uptake due to inability of cell penetration.
What drugs are Klebsiella sp. naturally resistant to and why?
Ampicillin (B- lactam) - because Klebsiella sp. produce protein that have affinity for, and destroys active Ampicilin before it reaches it PBP target.
what drugs are Stenotrophomonas maltophila naturall resistant to and why?
imipenam (B-lactam) - produces protein that destroy active imipenam (beta lactamases), before drug reaches it PBP target.
what drugs are lactobacilli & leuconostoc, naturally resisstant to and why?
Vancomycin - lac of appropriate cell wall precursor for Vancomysin to effectively attack and inhibit cell wall synth.
Examples of drug resistance target and mechanism.
-specialised proteins to inactivate drug.
-modify drug target.
-modified cell wall protein: (inhibit drug entry..)
-removal of antibiotic via efflux pump.
>(secondary> chromosome & plasmids)!!!!
what drugs are “pseudomonas aureginosa” naturally resistant to and why/how?
Sulfonamides, trimethoprim, tetracycline, or chloramphenicol -
-Lack of uptake resulting from inability of antibiotics to achieve effective intracellular concentrations
what drugs are enterococci sp. naturally resistant to, and
why/how?
All cephalosporins - Lack of PBPs that effectively bind and are inhibited by these beta lactam antibiotics
Aminoglycosides - Lack of sufficient oxidative metabolism to drive uptake of aminoglycosides
Not all resistance is required at the same rate, e.g. Resistance of S. aureus to penicillin:
– 1941 - 1%
– 1946 - 14%
– Now - >90%. ….. but what about Strep. pyogenes?
remained fairly susceptible.
+NO clear explanation as to why varying rates of resistance…
+Mutation or Transfer…
Aquired resistance mechanism -mutation e.g.
Mycobacteria ) resistance to Rifamycins and isolates of flouroquinolones, how so?
Rifamycins )point mutation on rifampicin binding region of rpoB
flouro’s)Predominantly mutation of the quinolone-resistance-determining- region (QRDR) of gyrA and parC/grlA
Acquired resistance - mutation of E.coli & Haemopillus influenzae….
-to trimethoprim, how so?
Mutations in the chromosomal gene specifying dihydrofolate reductase
Horizontal gene transfer - resistant of MRSA to methicilin, how?
Via acquisition of mecA genes which are on a mobile genetic element called “staphylococcal cassette chromosome” (SCCmec) which codes for penicillin binding proteins (PBPs) that are not sensitive to ß- lactam inhibition!
Horizontal gene transfer
Resistance of many pathogenic bacteria vs. sulfonamides, how?
Mediated by horizontal transfer for folP genes or parts of it.
Horizontal gene tranfer -
how does Enterococcus faecium and E. faecalis display resistance to vancomycin?
via acquisition of one of two related gene clusters vanA and van B, which code for enzymes that modify peptidoglycan precursor, reducing affinity to vancomycin.
What region of a for example: of R100 plasmid (typical resistance plasmid) is capable of addition/insertion of new resistance genes.
tra Operon, is the region of this plasmid able of carrying specific genes
Mechanism of resistance -how do bacteria prevent cell entry of antibiotic drugs,?
Gram-negative more intrinsically resistant due to outer membrane slows uptake
– E.g. Pseudomonas aeruginosa
• Mycobacteria impermeable to many drugs wall has high
lipid content
– E.g. Mycobacteria tuberculosis
Why do organisms form biofilms? Are there any advantages to this community ?
Via co-operative protein secretions that form a rigid symbiotic colony together.
it is 100-1000 times resistant to antibiotics.
Biopolymer matric reduces penetration efficiency.
what are the three stage of biofilm formation ?
1) attachment
2) growth
3) attachment
How do organism prevent cell entry of B-lactam and quinolones
Β-lactam and quinolones: decrease in porins
– Imipenem resistance to pseudomonas
How do organisms prevent cell entry of chloramphenicol ?
– plasmid that conveys impermeability
Aminoglycosides: Alter proteins that allow active transport e.g. Porins. In three main ways what are they?
- loss of porin
- narrowing of porin channel
- hypoexpression of porins within membrane
By what INTRINSIC methods do both gram positives and and gram negatives remove intracellular concentration of a drug.?
E.g. MexAB-OprM of P. aeruginosa (MEX multidrug efflux) antibiotics and disinfectants
Efflux, the active or facilitated/selective removal of agent from an controlled intracellular environment.
5 families of bacterial drug efflux pumps what are they?
• RND family drug exporters play a key role in clinically relevant resistance in Gram-negative bacteria
– ATP-binding cassette (ABC)
– Major facilitator superfamily (MFS)
– Multidrug and toxic compound extrusion (MATE)
– Small multidrug resistance (SMR)
– Resistance nodulation division (RND)
• The MFS, SMR and ABC are the major families responsible for drug efflux in Gram positive bacteria
What kind of efflux pump does S.aureus have?
MFS
Major facilitator superfamily (or)
Mothr Fuccing staph.
What kind of efflux subfamily does P.aureginosa and E.coli possess?
RND - resistance modulation Division
Or
P.E. RND
(Pseudomonas, Ecoli)
What subfamily of efflux pumps does L.lactis possess?
ABC - ATP- binding cassette
Or
Think “ Lacto drink” vit. a,b c
Other mechanism of resistance : modifying antibiotic in cell.
Please give an example ….
and feature genetics and habitat
β-lactamases degrade β-lactam antibiotics – Gram negative: wider range
• Either found on chromosome or often on Plasmids:
- commensal to pathogen
There are two type of betalactamase with regards to expression. They are “chromosome encoded” & “ plasmid mediated”.
What characteristics are typical of chromosome encoded expression?
Constitutive expression
– Often produced in small amounts
– Localise close to cell membrane
– Some organisms overproduce: P aeruginosa, Enterobacter, Acinetobacter
There are two type of betalactamase with regards to expression. They are “chromosome encoded” & “ plasmid mediated”.
What characteristics are typical of “plasmid mediated” expression ?
Most clinically relevant β-lactamases
– Transposons: chromosome plasmid
• Gram positives: Staphylococci: almost exclusively Streptococci: rare
TEM-1, is the most commonly encountered B-lactamase in gram negatives, which organism posses it and is expressed from plasmid or transpon
1) is widely spread and selected for and 2) is expressed both within plasmids and transposons,
What are the characteristics and examples of extended spectrum beta lactamases
– Affect cephalosporins
– CTX-M: >80 versions, found in Klebsiella sp. E.coli and
Salmonella - cefotaxime-hydrolysing
– SHV-1: >50 versions, Klebsiella
– OXA: poorly inhibited by clavulonic acid
– PSE: Pseudomonas carried, hydrolyse carbapenems as fast as
penicillin
Some B-lactamases require zinc to function
e.g. VIM, IMP, NDM (carbapenemase), what other characteristics define metalloproteinases ?
such as how does it resist penicillin?, what species process it? And how does science react?
bacteroides group
– Hydrolyse virtually all β-lactams including carbapenems
– Enzyme inhibitors offer no protection
Inhibited by the metal chelator EDTA
– Found in diverse range of organisms – Acinetobacter & P. aeruginosa,
Antibiotic modifying enzymes usually work in three ways:
What do they drugs catalyse at certain regions of active drug?
Acetylation (acetyltransferase)
Adenylation (adetyltransferase)
And phosphorylation (Phosphotransferase)
30 different enzymes and their variants have been identified…
