Antimicrobials and resistance

Lina Cavaco
Rene Hendriksen
Susanne Karlsmose Pedersen
Outline
• Antimicrobial resistance- definitions
• Basic types of resistance mechanisms
• Antimicrobial resistance- definitions
• Intrinsic resistance
• Acquired resistance
• Co and cross resistance- defintions
• Resistance mechanisms- examples and overview

E- learning
2 Module1
What is antimicrobial resistance
• Acquired
– Due to changes within an initially susceptible population
• Mutations (endogenous and vertically transmitted)
• Horizontal gene transfer

– Transformation

– Transduction

– Conjugation

E- learning
3 Module1
Three basic types of resistance
mechanisms (acquired)
• Reduced intracellular accumulation of the drug by decreased influx
and/or increased efflux of the drug

• Enzymatic incativation of drug

• Modification of the cellular target:

– Mutation
– Chemical modification
– Protection of the target site
– Overexpression of sensitive target for a more resistant one

E- learning
4 Module1
Intrinsic (natural) resistance
• Due to structural or functional trait allowing tolerance by all
members of a group (species, genus, etc)
– Inacessibility of the drug into the bacterial cell (Gram-negative cell
wall)
– Extrusion of the drug by chromosomally encoded active exporters
(Pseudomonas)

E- learning
5 Module1
Intrinsic (natural) resistance – cont.
• Innate production of enzymes that inactivate the drug
(Enterobacteriaceae beta-lactamase)
– Lack of affinity of the drug for the bacterial target (enterococcal gyrA)
– Lack of target (lack of cell wall in Mycoplasma)

E- learning
6 Module1
Factors affecting the level of resistance

• Natural level of resistance of the species

• Resistance gene or mutation involved

• Expression of the gene in strain

• Presence of other genes or mutations

E- learning
7 Module1
Example: Natural level of resistance
of the species
50
40
Species 1
30
Species 2
20
10
0
0,016 0,03 0,06 0,125 0,25 0,5 1 2 4 8 16 32 64 128 256

MIC mg/L

E- learning
8 Module1
What is cross-resistance
• Resistance to two related (avoparcin/vancomycin) or
unrelated drugs (erythromycin/lincosamides) due to a
single biological mechanism

E- learning
9 Module1
What is co-resistance

• Resistance to unrelated drugs (tetracyclines/sulphonamides) due

to different resistance mechanisms located in the same genetic
element

Origin

vanA tcr

erm(B)
E- learning
10 Module1
Antimicrobial resistance mechanisms

B
D

A
C

A- decreased cell permeability C- enzyme inactivation

B- alteration or replacement of the target D- active export
E- learning
11 Module1
 Resistance mechanisms
• Inactivation of the drug
– Penicillins, aminoglycosides

• Target modification
– Tetracyclines, fluoroquinolones

• Target replacement
– mecA

• Drug trapping or titration - hyperproducers

– Penicillins, sulphonamides

E- learning
12 Module1
Overview of microbial drug resistance
Chromosome and Inner Cell Outer
Permeability and
cytoplasm membrane wall membrane porin deficiency
New or (Gram-)
mutated PBPs Penicillins
RNA
Reduction Cephalosporins
Polymerase Penicillin Monobactams
mutations Nitroimidazoles Cephalosporins Carbapenems
Rifamycin Modifying Quinolones
Monobactams Aminoglycosides
enzymes
DNA gyrase Tetracyclines
Carbapenems
and Aminoglycosides
topoisomera Chloramphenicol Beta-lactamases Membrane pumps
se IV Fosfomycin
mutations Streptogramin A Penicillin Tetracyclines
Tetracyclines Fusidic acid
Quinolones Cephalosporins
Rifamycins Quinolones
Novobiocin Monobactams Bacitracin
Ribosomal
Acquired Chloramphenicol
mutations and Carbapenems
metabolic Lincosamides
modification
bypass Acquired Betalactams
Aminoglycosides Aminoglycosides
ligases
Sulphonamides Macrolides
Trimethroprim Vancomycin Multi-drug Antiseptics
Mupirocin
13 resistance
Teicoplanin
 On behalf of the EURL-AR team:
Thank you very much!

www.antimicrobialresistance.dk

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