Antimicrobials resistance -

introduction to causes and mechanisms

Lina Cavaco
Rene Hendriksen
Susanne Karlsmose Pedersen
Outline
• Antimicrobial resistance- basis for resistance
• Point mutations
• Resistance genes
• Non-genetic mechanisms

• Examples

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Basis for resistance
• Genetic basis:
– Chromosomal due to spontaneous mutation
• In target molecule
• In drug uptake system
• In regulatory system

– Plasmid-mediated
• Possibly transferred via conjugation
• Leading to multidrug resistance

– Located on another type of mobile genetic element, e.g. transposons,

integrons, gene cassettes E- learning
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Basis for resistance
• Non-genetic mechanisms
– Inacessibility to drugs (abcess, TB-infection)
– Stationary phase (not susceptible to inhibitors of cell wall synthesis)
– Protoplasts and spheroplasts (no cell wall)

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 Genetic variations/point mutations
• DNA gyrase - quinolone resistance Enterobacteriaceae
110 120 130 140 150
NalS 101 TGACGTAATC GGTAAATACC ATCCCCACGG CGATTCCGCA GTGTATGACA
NalR MUT83A 101 TGACGTAATC GGTAAATACC ATCCCCACGG CGATTACGCA GTGTATGACA
NalR MUT83T 101 TGACGTAATC GGTAAATACC ATCCCCACGG CGATTTCGCA GTGTATGACA

Codon 83: TCC Ser

TTC Phe
TAC Tyr

Chromosomal mutations rarely spread horizontally

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Acquired resistance mechanisms I
Point mutations in target genes

Up-regulated multi-efflux pump

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Acquired resistance mechanisms II
Acquired genes Modification
of drug

Replacement/
protection of
target

Lowering
concentration
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 Example: Tetracyclines - mechanism of action
Broad spectrum antibiotics:
Active against many Gram-negative and Gram-positive bacteria,
cell wall-free mycoplasma, chlamydia, rickettsia and protozoa

30S
DNA 50S
mRNA

Active transport (carrier mediated)

Passive diffusion tetracyclines
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Tetracycline resistance
- mechanisms in bacteria
Active efflux:
tet(A), tet(B), tet(C), tet(D), tet(E), tet(G), tet(H), tet(I), tet(J), tet(Y), tet(30),
tet(31), tet(K), tet(L), tet(V), tet(Z), tetP(A), tcr3, otr(B), tet(33), tet(35),
tet(38), tet(39)
Ribosomal protection:
tet(M), tet(O), tet(Q), tet(S), tet(T), tet(W), tetP(B), otr(A), tet, tet(32), tet(36)
Enzymatic modification:
tet(X), tet(34), tet(37)
Unknown:
tet(U), otr(C) E- learning
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 One Various Many
drug mechanisms bacteria

Variable
phenotype

Variable
clinical
importance

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 Ex: Beta-lactam resistance
Mode of acquisition Mechanism Bacterial species
None Reduced permeability Pseudomonas spp.
Enterobacteriaceae
Conjugation Enzymatic inactivation
Staphylococci
Unknown Target replacement Staphylococci

Transformation Target modification Streptococci

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 On behalf of the EURL-AR team:
Thank you very much!

www.antimicrobialresistance.dk

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