Course: Current Topics in the Molecular Life Sciences Instructor of Record: Prof. M.S.

Ullrich

Nature Reviews Microbiology 4, p. 629-636 (August 2006)

presented by Miriam Masud

 Introduction
• Synopsis: MDR efflux pumps associated
with pathogenicity as well as resistance

• Evidence: MDTs extrude virulence

molecules

• Importance: increased medical relevance

Bacterial MDR Pump Families
Bacterial MDR Pump Families
 Investigation Process:
• Construct pump mutants
• Observe pathogenicity in suitable model

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Examples
•www.feuerbrand.de/feuerbrand/allgemein.html

Erwinia amylovora

• Causes fire blight in apple and pear

trees
Phytoalexins
• AcrAB pump (RND):
– AcrB mutant susceptible to antimicrobial
compounds from leaves, reduced
infection and survival
– AcrAB expression doubled in growth in Bacterial antibiotics
tissue

→ AcrAB in resistance to host

compounds

• NorM pump (MATE) allows resistance to

antibiotics from other bacteria
www.ehagroup.com/epidemiology/illnesses/images/pseudomonas-aeruginosa.jpg

Pseudomonas aeruginosa

• Opportunistic pathogen: tissue

infections and pneumonia
• MexAB-OprM deletion impairs
invasion of MDCK epithelial cells
Virulence determinants
– Complementation restores phenotype

→ pump may export virulence

determinants
• Also: acute pneumonia correlates to
overexpression (rats)
• However, overexpression can
decrease virulence: quorum sensing
and excessive efflux
www.shardcore.org/painting/salmonella.jpg

Salmonella typhimurium
(S. enterica serovar typhimurium)

•Causes gastroenteritis
•Overexpression of AcrB
correlated to resistance Bile and ?

•AcrB needed for adherence and

invasion (mouse macrophage),
colonisation and persistence
(chickens)
•Ruffling mediated by Type III SS
products, not seen in acrB deletion
mutants
→ AcrB disruption may affect
www.med.yale.edu

Type III secretion of toxins

 www.birdfluinsider.com/images/penicillin.jpg
Development of clinical resistance

• Environmental organisms
produced antimicrobial
compounds
• Pumps evolved for host
colonisation
• Clinical antibiotic use
selected for resistant
phenotypes (upregulated
MDTs)
 Remarks
“In a recent collection of soil-dwelling Streptomyces, every organism was
multidrug resistant. Most were resistant to at least seven different
antibiotics (D'Costa et al., 2006) … These data not only suggest that
our surroundings can act as a reservoir for new (and old) resistance
mechanisms, but that the drugs we use to treat infectious diseases have
long-lasting effects outside of the hospital. Many antimicrobial molecules
exist for millennia stably within the environment (Cook et al., 1989),
where they select and promote growth of resistant strains.”
- Alekshun and Levy

“It is proposed that the primary biological role of most MDR systems in
Streptomyces species is not removal of extrinsic drugs, but rather export
of specific toxic compounds endogenously synthesized during
growth.”
- Lee et al
 Conclusions
• Expanded roles of MDT:
– Resistance to host and other compounds
– Secretion of virulence factors
• (adhesins, toxins)
• Type III SS link?
– Quorum sensing

• Holistic understanding
Thank you!
 References
Alekshun, M.N and Levy, S.B. (2007) Molecular mechanisms of
antibacterial multidrug resistance. Cell 128, p. 1037-1050
Lee, L., Chen, Y., Kirby, R., Chen, C. and Chen, C.W. (2007) A
multidrug efflux system is involved in colony growth in Streptomyces
lividans. Microbiology 153 p. 924-934
www.med.yale.edu
www.shardcore.org/painting/salmonella.jpg
www.ehagroup.com/epidemiology/illnesses/images/pseudomonas-
aeruginosa.jpg
www.hiiret.fi/pics/taustahiiret.jpg
www.maf.govt.nz/photos/gifs/93.jpg
www.birdfluinsider.com/images/penicillin.jpg
www.feuerbrand.de/feuerbrand/allgemein.html
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