Out With the Bad: Efflux in Klebsiella pneumoniae

Phagehunter.org is proud to announce an article by guest author, E. Ohneck, of Emory University, as she discusses the importance of efflux pumps in bacterial systems.

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The Resistance-Nodulation-Division (RND) family of efflux pumps is widely utilized, especially among Gram-negative bacteria, for the export of a diverse array of antimicrobial agents from the bacterial interior, making these efflux systems important in multidrug resistance (1). RND family pumps are composed of three parts: a transporter protein in the inner cytoplasmic membrane, an outer membrane protein channel, and an accessory protein that connects the two (1). The AcrAB-TolC efflux pump is one such efflux system found in multiple Gram-negative bacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (1).

In their recent study, presented in a paper entitled “Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence,” Padilla et al confirm a role in multidrug resistance for the AcrAB-TolC efflux pump of K. pneumoniae, a highly prevalent nosocomial enterobacterial pathogen responsible for both urinary tract infections and bacterial pneumonia.

Through the use of knockout strains deficient in AcrB, the transporter protein component of the pump, the authors show the importance of AcrAB-TolC in resistance to β-lactams, aminoglycosides, quinolones, and other antibiotics (2). Interestingly, these AcrB knockouts were also significantly more susceptible to human antimicrobial peptides and were less able to colonize mice lungs and cause pneumonia, effects which were shown to be attributable to AcrAB-TolC deficiency (2).

These results have several important implications. First, like other RND family efflux pumps, the AcrAB-TolC efflux pump likely contributes significantly to the multidrug resistant phenotype observed in some K. pneumoniae strains, due to its broad antimicrobial substrate specificity (2). Secondly, AcrAB-TolC may also mediate resistance to host antimicrobial peptides (2). To date, this phenomenon has been established for relatively few efflux pumps, one of the best characterized examples being MtrCDE-mediated resistance to the host antimicrobial peptide LL-37 in Neisseria gonorrhoeae (3). The ability of bacterial efflux systems to pump out host-derived antimicrobial agents provides pathogens with an important mechanism of protection against one of the first-line defenses of the innate immune system.

Taken together, these conclusions raise the concern that antibiotic treatment can select not only for increasingly antibiotic resistant strains, but also for strains better able to resist the host immune defenses, and thus better able to cause disease. Clearly, efflux-mediated resistance to host antimicrobial compounds and its relation to antibiotic resistance and pathogenesis is an area that demands further study in order to develop efficient methods of combating the increasing number of multidrug resistant bacteria.

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Sources:
1. Piddock LJV. Multidrug-resistance efflux pumps—not just for resistance. Nat Rev Microbiol. 2006 Aug 4(8): 629 – 36.

2. Padilla E, Llobet E, Doménech-Sánchez A, Martínez-Martínez L, Bengoechea JA, & Albertí S (2009). Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. Antimicrobial agents and chemotherapy PMID: 19858254

3. 3. Shafer WM, Qu X, Waring AJ, Lehrer RI. Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1829-33.

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Other Articles of Interest:
The Origins of Antibiotic Resistance
Wild Bacteria that eat Our Antibiotics? Of Course!
Antibiotic Treatment: Increasing the Rate of Genetic Exchange

A Home for the Bugs in Our Appendix

The appendix has long been considered a useless, vestigial organ, primarily based on the fact that it can be removed with no visibly harmful effects on the appendectomy recipient and that it is rather susceptible to severe inflammation. In fact, many theories have been proposed for its ancient purpose, ranging from being a place to allow plant matter to ferment to being a locale for crushed bones to be dissolved.

However, recent evidence posits that the appendix plays a crucial role in maintaining important gut symbionts. A recent report by Smith et al compares the structural features of the appendix across various mammalian species, and uses this comparison to further elucidate the function the appendix.

It has been known for a few years that the lymph tissue in the appendix has played an important role in the immune-regulation of gut symbionts. The tissues in the appendix actively promote and support biofilm growth with various secreted effectors to a significantly greater degree than the rest of the gut.

Structurally, the appendix is in relative isolation from the rest of the gut, bounded by a rather constricted opening and narrow lumen. This, coupled with the above observations, suggest a role for the appendix in maintaining important gut symbionts during in an immune response to gut pathogens, or to the diarrheal effects of certain pathogens. Due to the unique structure of the appendix, symbionts within this structure would be more likely to survive such conditions and be capable of re-colonizing the gut following pathogen clearance.

The authors show, through comparative structural analysis, that in many mammals the structure of the appendix is similar, with differences occurring due primarily to the greater gut structure (a product of the mammals diet). Furthermore, they show that some animals may have lost the appendix, but that in other clades, its presence has been maintained for tens of millions of years.

Ultimately, these observations show that the appendix is far from useless and vestigial. Though this does raise questions about those individuals who have had their appendix removed. Is there a higher incidence of post-antibiotic treatment Clostridium difficle infections, or inflammatory bowel diseases? Or are appendix-less individuals more susceptible to adverse reactions and longer recovery times following diarrheal illnesses like norovirus, Salmonella, or cholera infections?

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Citation:
Smith HF, Fisher RE, Everett ML, Thomas AD, Bollinger RR, & Parker W (2009). Comparative anatomy and phylogenetic distribution of the mammalian cecal appendix. Journal of evolutionary biology, 22 (10), 1984-99 PMID: 19678866

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Other Articles of Interest:
A MAP to Crohn's Disease; Revisiting Koch's Postulates
Altruism in Bacteria? Allowing Yourself to Die for the Good of the Species