ANTIBIOTIC RESISTANCE: IS IT INEVITABLE?
The human race is at an evolutionary advantage over other organisms. From complex surgeries, to secure habitats, accessible nutrition and weapons capable of destroying the planet as we know it, we humans like to believe we are in complete control. However, one race we might not end up on top of, is bacterial resistance to our strongest antibiotics. Antibiotics are crucial in ensuring our ability to fight off infections when our immune system is not able to independently. The drugs disrupt pathways in bacterial cell division, membrane synthesis, translation in a wide array of bacterial species, or to more specific strains. Some bacterial strains are evolving resistance at a faster rate than we are able to synthesize new drugs. Why is resistance spreading at alarming rates? How will this affect us in the near future? And can we come up with new solutions to this problem?
In 1928, Alexander Fleming discovered the first antibiotic agent, Penicillin. He was conducting an experiment with Staphylococcus aureus when he realized there was a moldy petri dish, in which S. aureus was not growing. The mold was identified as Penicillium notatum, and the isolation of penicillin from the mold allowed us to use the agent to our benefit. (Demain & Sanchez, 2009) Since then, many new agents were isolated from other naturally occurring organisms. Today, there are more than 100 different antibiotics grouped into seven major families, each targeting a major pathway crucial to bacterial cell growth and division. However, bacteria are rapidly evolving organisms. We use them as a model to study different pathways and behaviors, because of how fast they replicate and mutate. A single petri dish with a single strain streaked on it can have thousands of distinct colonies. The more variation exists in a population, the more likely it is, that there exists a mutation capable of inactivating or fighting off an antibiotic, making it resistant. It does not stop there, however. Bacteria are capable of horizontal gene transfer which makes a resistant mutation spread through the population and make the entire population resistant. “The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission.” (J. Davies & D. Davies, 2010)
The synthesis of new antibiotics over the decades is causing multidrug-resistant bacteria. This is especially prevalent in hospitals where the strongest drugs are used. (H. Neu, 1992) In 1941, virtually all strains of Staphylococcus aureus were susceptible to penicillin G, however by 1944 S. aureus evolved the enzyme penicillinase, also known as b-lactamase which inactivates the antibiotic. (H. Neu, 1992) In 1992, 95% of S. aureus was resistant to penicillin. More recently, MRSA has been a major threat. MRSA is S. aureus that is resistant to penicillin methicillin, cephalosporins and our strongest used drugs, carbapenems. There are many reasons for this rapid spread of resistance. Doctors are overprescribing antibiotics, while patients are not finishing their doses because they start feeling better. Farmers spread antibiotics to save their crops, but contaminate the waterways which provide bacteria with subinhibitory concentrations of the drug. (A. Rodríguez-Rojas, J. Rodríguez-Beltrán, A. Couce, J. Blázquez, 2013) Presenting bacteria with concentrations lower than the minimum inhibitory concentration is comparative to vaccinating a child. The bacteria become resistant because it is able to survive with such low concentrations of the drug, and evolves a defense which it stores in plasmids or in its main DNA for when higher concentrations of the drug are presented. Nowadays, there is also a shortage of new antibiotics being synthesized, as a result of our capitalist economy. “Unfortunately, most of the large pharmaceutical companies have abandoned the search for new antimicrobial compounds … Drugs directed against chronic diseases offer a better revenue stream than do antimicrobial agents, as for the latter the length of treatment is short and government restriction is likely.” (Demain & Sanchez, 2009)
These multidrug-resistant bacteria are motivating more microbiologists to find new solutions to this nonending evolutionary arms race. It is a cultural evolution in regards to Humans while being genetic in regards to the Bacteria. One distinct solution being researched is the idea that multidrug-resistant bacteria or ‘Superbugs’ overexpress a pump called AcrAB-tolC. This pump in Escherichia coli is made of three proteins in a complex, AcrA, AcrB and TolC. Superbugs use this protein complex to pump out antibiotics, other toxins, and metabolites out of the cell. (C Ruiz & S Levy, 2013) By finding compounds and metabolites that bind to this pump, we can regulate the pump by competitively inhibiting it, forcing the antibiotics inside the cell long enough to damage the cell. This inhibition would increase the efficiency of b-lactams, fluoroquinolones, and tetracyclines, which are three antibiotic families.
Antibiotic resistance is a threat to our existence and well being. The arms race between bacteria and humans might never end, however, we cannot afford to slow down our efforts in synthesizing new drugs and new ways of fighting off infections. We can all help slow down resistance by adopting better hygiene, finishing our prescribed antibiotic pills, and not pressuring doctors to prescribe antibiotics if not necessary.
Example of antibiotic resistance. The way we test for resistance is by streaking a lawn of a single strain of bacteria on an agar plate and place these antibiotic disks throughout the plate. Each disk is a single type of antibiotics, and it is diffused on to a plate. The closer to the disk, the higher the concentration of antibiotics diffused on the agar. On the left, we observe see-through areas around these antibiotic disks. The bigger this area, the more susceptible the bacteria is to the antibiotic. Our problem is that bacteria strains are evolving, and our results are looking more like what is on the right plate. The area has shrunk for most antibiotics and looks to be useless for 4 of the antibiotics.
Citations:
1) Ruiz, C. and Levy, S.B., 2013. Regulation of acrAB expression by cellular metabolites in Escherichia coli. Journal of Antimicrobial Chemotherapy, 69(2), pp.390-399.
2) Neu, H.C., 1992. The crisis in antibiotic resistance. Science, 257(5073), pp.1064-1073.
3) Davies, J. and Davies, D., 2010. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev., 74(3), pp.417-433.
4) Stokes, H.W. and Gillings, M.R., 2011. Gene flow, mobile genetic elements and the recruitment of antibiotic resistance genes into Gram-negative pathogens. FEMS microbiology reviews, 35(5), pp.790-819.
5) Rodríguez-Rojas, A., Rodríguez-Beltrán, J., Couce, A. and Blázquez, J., 2013. Antibiotics and antibiotic resistance: a bitter fight against evolution. International Journal of Medical Microbiology, 303(6-7), pp.293-297.
6) Demain, A.L. and Sanchez, S., 2009. Microbial drug discovery: 80 years of progress. The Journal of antibiotics, 62(1), p.5.