Multidrug resistance (MDR) has become a more and more prevalent issue within the last few months, as authorities say humanity has reached the post-antibiotic era, as opposed to approaching it (PBS, 2013). While currently considered to be an everyday commodity, antibiotics are important tools that form the basis of modern medicine, as they are essential in treating infections that may otherwise be fatal (CDC, 2013). In order to tackle this widespread issue, it is important to understand the underlying mechanisms that allow bacteria to become resistant. Efflux pumps are an important group of proteins associated with MDR.
Efflux pumps are a group of transport proteins found in the membrane of bacteria that expel target molecules through active transport. These targets are usually toxic to the bacteria, and naturally include antibiotics (Webber, 2002). Efflux pumps are found throughout the prokaryotic kingdom, and are a common type of resistance to antibiotics. Before exposure, their effects were generally limited to environmental toxins. For example, AcrAB is an efflux pump responsible for the removal of bile acids from E. coli (Fernandez & Hancock, 2012). However, efflux pumps have developed mutations over time with respect to antibiotic exposure. Specifically, efflux pumps have developed specificity in protein structure, and adapted to using the target antibiotic as an inducer of pump expression. The plasmids coding for pumps that target specific antibiotics can then be shared to surrounding bacteria through lateral gene transfer. Bacteria can share their resistant efflux pumps, but of even more importance is that the efflux pumps themselves can target classes of antibiotics, instead of being drug-specific (Webber, 2002). In this way, MDR is spread quickly among individual bacterium.
Of all the classes of efflux pumps, the resistance-nodulation cell division (RND) class is the most clinically relevant, as the majority of antibiotic specific pumps are from this class. All pumps of this class have a tripartite structure: the inner membrane pump protein , the membrane fusion protein, and the outer membrane protein. The inner membrane pump is usually a trimer (Fig 1), and each monomer is protonated in a rotational fashion, which activates the monomer to bind to the substrate. Once un-protonated, the bond is broken, but the substrate is now in the efflux complex, and can be transported out. The membrane fusion protein works to bring the 2 membranes of a gram-negative bacterium together, which connects the outer membrane protein with the inner membrane pump. The outer membrane protein is usually composed of a beta barrel in the outer membrane, connected to an helical barrel in the periplasmic space, as seen in Figure 2 (Nikaido & Takatsuka, 2009). The outer membrane acts as a channel to remove the target molecule from the cell. The whole complex can be seen in Figure 3. All parts of this efflux complex have been shown to be essential to the function of pump, which may be important when identifying drug targets. The beta barrel of the outer membrane protein may be a key target, as it is the only portion that sticks out of the cell, making it easily accessible to a drug.
Efflux pumps have the potential to be important drug targets to supplement current antibiotics. Current work on targeting efflux pumps have been relatively new, and not much has been done in the development of drugs. The identification and explanation of resistance mechanisms is an essential part of understanding MDR, and it has clear clinical applications that are required to combat antibiotic resistance today.
Works Cited:
CDC. (2013). Antibiotic resistance threats in the United States, 2013.
Fernandez, L., & Hancock, R. E. W. (2012). Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance. Clinical Microbiology Reviews, 25(4), 661–681. doi:10.1128/CMR.00043-12
Nikaido, H., & Takatsuka, Y. (2009). Mechanisms of RND multidrug efflux pumps. Biochimica et Biophysica Acta (BBA) – Proteins and Proteomics, 1794(5), 769–781. doi:10.1016/j.bbapap.2008.10.004
PBS. (2013). Dr. Arjun Srinivasan: We’ve Reached “The End of Antibiotics, Period.” PBS Frontline. Retrieved from http://www.pbs.org/wgbh/pages/frontline/health-science-technology/hunting-the-nightmare-bacteria/dr-arjun-srinivasan-weve-reached-the-end-of-antibiotics-period/
Webber, M. A. (2002). The importance of efflux pumps in bacterial antibiotic resistance. Journal of Antimicrobial Chemotherapy, 51(1), 9–11. doi:10.1093/jac/dkg050