The Threat of Multidrug-Resistant Bacteria
Since their introduction in the 1940s, antibiotics have been one of our most successful classes of drugs, saving millions of lives. However, we observe bacterial antibiotic resistance to these drugs with increasing frequency. Since antibiotics kill bacteria, this effect results in an enormous selective pressure for the bacteria to acquire genes capable of ensuring survival. While such gene acquisition events (i.e., horizontal gene transfer) are rare, they need only occur once and resistant bacteria can then proliferate. We are now observing infections that can be treated with only a few “last resort” antibiotics and it is feared that within a few decades we may return to a pre-antibiotic era where infectious diseases were a leading cause of death.
Beginning in the 1940s, the modern era of antibiotic development began with the discovery and production of penicillin (nicely described in (4)). Penicillin was considered a wonder drug at the time and it saved the lives of tens of thousands of Allied soldiers during World War II. However, bacterial strains exhibiting resistance to penicillin were observed within a year or two of its use. Resistance was found later to be due to the acquisition of the bla gene encoding β-lactamase. The 1940s and 1950s have been referred to as the “golden age” of antibiotic development with the discovery of numerous drugs including tetracyclines, aminoglycosides such as kanamycin, β-lactamase-resistant β-lactams, including methicillin and carbapenem, glycopeptides, including vancomycin, fluoroquinolones and cationic peptides such as polymyxins. Some in the medical profession believed we had conquered infectious diseases once and for all (9). Research into antibiotics slowed as the pharmaceutical industry began to focus on other conditions such heart disease, AIDS and cancer. Following the “golden age”, no new broad-spectrum antibiotics were discovered for 50 years. However, while antibiotics were plentiful, resistance was observed for each antibiotic introduced into clinical use. Today we are seeing bacterial species with multidrug resistance and new antibiotics only rarely developed for medical application.
State of antibiotic resistance today
It is estimated that antibiotic resistance results in over 700,000 deaths worldwide per year and this number may increase to as many as ten million by the year 2050. Recently, the World Health Organization published a list of 12 multidrug-resistant bacterial species that represent the most significant danger to human health. Resistant bacteria capable of causing life-threatening illnesses in hospitals and nursing homes were deemed of utmost critical importance. Included in the list were Pseudomonas aeruginosa, which causes tissue and bloodstream infections sometimes resulting in septic shock, Klebsiella pneumoniae, which causes pneumonia, bloodstream infections, urinary tract infections, meningitis and liver abscesses and Staphylococcus aureus, which causes skin and bloodstream infections. Other species of bacteria on the list cause food poisoning and gonorrhoea. In a terrifying development, a woman in the United States died in 2016 of an infection of K. pneumoniae in which the bacterium was found to be resistant to all 26 available antibiotics that were tested (2).
Solutions for treating antibiotic-resistant bacterial infections
The scientific community is actively searching for solutions to the problem of antibiotic resistance. An approach often used is antibiotic “tailoring” where new generations of synthetic antibiotics are produced from modifications made to a small number of naturally occurring scaffolds such as penicillin, quinolones and macrolides (3). However, the number of new drugs produced in this manner is not expected to be limitless. Another approach is to develop antibiotic adjuvants or “helper” drugs that, while not antibiotics themselves, have the ability to resensitize resistant bacteria to certain antibiotics (6). Another approach is to identify new antibiotic targets. Most antibiotics developed so far target only a few essential bacterial processes such as peptidoglycan synthesis, protein synthesis, DNA replication and transcription. Recently identified targets include the cell division apparatus (5), the assembly of the Gram-negative outer membrane (10) and quorum sensing (1, 8). Finally, it may be possible to develop agents that target bacterial virulence. Most bacteria produce secreted or cell surface proteins that target different facets of our immune response, disabling the defences that normally keep us disease free. By targeting the production or the action of these “effector” proteins, we may be able to allow our immune system to eradicate pathogens without the use of antibiotics. Such a strategy is attractive because it is not expected to introduce a selective pressure for survival by the bacteria and a need to acquire resistance. However, to date no such drugs have emerged from the drug pipeline (7).
1. Boyaci, H., T. Shah, A. Hurley, B. Kokona, Z. Li, C. Ventocilla, P. D. Jeffrey, M. F. Semmelhack, R. Fairman, B. L. Bassler, and F. M. Hughson. 2016. Structure, Regulation, and Inhibition of the Quorum-Sensing Signal Integrator LuxO. PLoS Biol 14:e1002464.
2. Chen, L., R. Todd, J. Kiehlbauch, M. Walters, and A. Kallen. 2017. Notes from the Field: Pan-Resistant New Delhi Metallo-Beta-Lactamase-Producing Klebsiella pneumoniae - Washoe County, Nevada, 2016. MMWR Morb Mortal Wkly Rep 66:33.
3. Fischbach, M. A., and C. T. Walsh. 2009. Antibiotics for emerging pathogens. Science 325:1089-1093.
4. Forest, K. T., and A. M. Stock. 2016. Classic Spotlight: Crowd Sourcing Provided Penicillium Strains for the War Effort. J Bacteriol 198:877.
5. Haydon, D. J., N. R. Stokes, R. Ure, G. Galbraith, J. M. Bennett, D. R. Brown, P. J. Baker, V. V. Barynin, D. W. Rice, S. E. Sedelnikova, J. R. Heal, J. M. Sheridan, S. T. Aiwale, P. K. Chauhan, A. Srivastava, A. Taneja, I. Collins, J. Errington, and L. G. Czaplewski. 2008. An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science 321:1673-1675.
6. Jana, B., A. K. Cain, W. T. Doerrler, C. J. Boinett, M. C. Fookes, J. Parkhill, and L. Guardabassi. 2017. The secondary resistome of multidrug-resistant Klebsiella pneumoniae. Scientific Reports 7:42483.
7. Maura, D., A. E. Ballok, and L. G. Rahme. 2016. Considerations and caveats in anti-virulence drug development. Curr Opin Microbiol 33:41-46.
8. O'Loughlin, C. T., L. C. Miller, A. Siryaporn, K. Drescher, M. F. Semmelhack, and B. L. Bassler. 2013. A quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence and biofilm formation. Proc Natl Acad Sci U S A 110:17981-17986.
9. Pier, G. B. 2008. On the greatly exaggerated reports of the death of infectious diseases. Clin Infect Dis 47:1113-1114.
10. Srinivas, N., P. Jetter, B. J. Ueberbacher, M. Werneburg, K. Zerbe, J. Steinmann, B. Van der Meijden, F. Bernardini, A. Lederer, R. L. Dias, P. E. Misson, H. Henze, J. Zumbrunn, F. O. Gombert, D. Obrecht, P. Hunziker, S. Schauer, U. Ziegler, A. Kach, L. Eberl, K. Riedel, S. J. DeMarco, and J. A. Robinson. 2010. Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa. Science 327:1010-1013.