Course: Current Topics in the Molecular Life Sciences Ullrich

Instructor of Record: Prof. M.S.

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

→ AcrAB in resistance to host
compounds

NorM pump (MATE) allows resistance to antibiotics from other bacteria

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Pseudomonas aeruginosa
• • Opportunistic pathogen: tissue infections and pneumonia MexAB-OprM deletion impairs invasion of MDCK epithelial cells
– Complementation restores phenotype
Virulence determinants


• •

pump may export virulence determinants

Also: acute pneumonia correlates to overexpression (rats) However, overexpression can decrease virulence: quorum sensing and excessive efflux

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Salmonella typhimurium
(S. enterica serovar typhimurium)

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

→ AcrB disruption may affect Type III secretion of toxins

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Development of clinical resistance • Environmental organisms produced antimicrobial compounds • Pumps evolved for host colonisation • Clinical antibiotic use selected for resistant phenotypes (upregulated MDTs)

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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/pseudomonasaeruginosa.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 www.photopix.de/images/uploads/klarsreuti-0069-20051027.jpg