week 5: antimicrobial resistance

What is antimicrobial resistance (AMR)?

ability of bacteria to resist effects of antimicrobials

What is biological resistance?

changes that result in reduced susceptibility of organism to particular antimicrobial

What is clinical resistance?

susceptibility lost to extent drug can no longer be effective for clinical use

T/F clinical resistance is an ongoing process

F, bio resistance

What 3 factors influence antimicrobial resistance?

drug, environment, microorganism

What is environmentally mediated antimicrobial resistance?

resistance directly resulting from physical/chemical characteristics of environment that either alter antimicrobial or microorganism’s response to drug

What are examples of environmentally mediated antimicrobial resistance?

erythromycin and aminoglycosides diminish in decreasing pH

tetracycline diminish in increasing pH

aminoglycosides affected by absence O2 and [cations] in environment

Is gentamicin more effective at low or high pH?

high

Provide an example of environmental factors involving aminoglycosides and P aeruginosa

cations (Mg and Ca) compete with aminoglycosides for binding sites on outer membrane of P aeruginosa

if cations win, less drug is taken up

What is microorganism-mediated antimicrobial resistance?

results from genetically encoded traits of microorganism

intrinsic or acquired

What is intrinsic resistance?

result from normal genetic state (natural)

predictable patterns, help in ID

What is acquired resistance?

altered cell physiology and structure caused by mutations or exchange

unpredictable

How are resistance genes transferred?

genes on plasmids or transposons that are transferred horizontally

Provide 3 examples of horizontal gene transfer

1. direct exchange (conjugation)

2. bacteriophage (transduction)

3. acquisition of DNA (transformation)

How does bacterial conjugation occur?

via sex pili or mating bridge

How does transduction occur via bacteriophage?

1. phage infects cell

2. make phage DNA/proteins

3. donor cell lyses and releases

4. infects other host cells

5. recombination can occur

How does genetic transformation in bacteria occur?

1. recipient cell takes up donor DNA

2. DNA aligns with complementary bases

3. recombination occurs

What are some examples of resistance mechanisms?

• decreased ABX uptake (block entry)

• produce enzyme that inactivate ABX

• alter target site

• increase efflux of ABX

What is SMR? What efflux transporter?

small multidrug resistance family (ex: tetracycline, sulfonamides)

go through QacC

What is MFS? What efflux transporter?

major facilitator superfamily (ex: fluoroquinolones, tetracycline)

go through NorA and OMP

QaaC and NorA are

H+ transporters

What is ABC? What efflux transporter?

ATP-binding cassette superfamily (fluoroquinolones, tetracyclines)

go through PatA

PatA is 

ATP mediated

What is MATE? What efflux transporter?

multidrug and toxic compound extrusion family (fluoroquinolones, aminoglycosides)

NorM

NorM is

Na+/H+ transporter

What is RND? What efflux transporter?

resistance-nodulation-division family (lots)

TolC-AcrB-AcrA transporter

What are the 3 types of resistance to B lactams?

1. enzymatic destruction (B lactams)

2. altered target (PBPs)

3. decreased uptake (changes in outer membrane porins in gram -)

What do B lactmases do the B lactam ABX?

open B lactam ring and alter structure so no bind to PBPs

result: cell wall synthesis continues

What enzyme is active against carbapenem drugs?

carbapenemase

What are extended spectrum B-lactamses?

derived from B lactamase, confer resistance to penicillin and cephalosporin

How does the target of B lactams alter?

the bacteria changes of acquires from other bacteria genes that encode altered PBPs (cell wall)

the PBPs can function in the presence of ABX

Provide 2 bacteria species that are resistant to B lactams from altered targets.

S aureus resistant to methicillin

MRSA

Describe how decreased uptake of B lactams results in resistance

in gram - bacteria, changes to outer membrane porins that B lactams use to enter the cell = resistance

Which bacteria species has acquired high level of resistance to vancomycin?

enterococci, through glycopeptides

What is the MOA of glycopeptides?

bind aa in cell wall to prevent new peptidoglycan

What are the 3 resistance mechanisms to aminoglycosides (ex: gentamicin, tobramycin)?

1. enzyme mods

2. altered target

3. decreased uptake

How does enzyme modification alter aminoglycoside molecules?

ex: phosphorylation, adenylation, acetylation

modified = decreased affinity to 30S ribosome unit = protein synthesis can continue

How does altered target impact aminoglycosides?

mutations in ribosomal binding site diminish aminoglycoside binding/activity

Describe how decreased uptake pathways impact aminoglycosides.

changes in # or characteristics of outer membrane porins = resistance

Why is ABX resistance on the rise?

ABX misuse (selects for resistant mutants)

What are examples of misuse?

using ABX for colds or viral infections, in animal feed or using someone else’s RX