by Soo Yeon (Nancy) Kim, Justin Wang, and Zaeem Nazir
Antibiotic resistance is the ability for bacteria to withstand antibiotics by evolving into mutant strains that can survive exposure to antibiotics. However, researchers have overlooked studies on how there are some bacteria with no genetic resistance to antibiotics are able to survive even though they are not supposed to. Specifically, understanding the cell cycles of these “persistent bacteria” has gained more interest as an alternative way of controlling and even killing bacterial populations. Consequently, the two papers “Bacterial Persistence as a Phenotypic Switch” and “Non-inherited Antibiotic Resistance,” suggest that bacterial persistence is caused by oscillating stages of replication and non- replication in the cell cycle, meaning varying levels of reproductive ability.
These two papers utilize several methods to investigate the non-inherited antibiotic resistance of single cell bacteria. In “Bacterial Persistence as a Phenotypic Switch,” researchers use microfluidic devices. These microfluidic devices were used in combination with time-lapse microscopy which allowed the growth of bacterial colonies to be observed over time when exposed to antibiotic pressure. The bacterial density was represented linearly, and longer fluorescent lines suggest larger colonies, and the reappearance and elongation of the lines reflects the repopulation done by persistent bacteria. On the other hand, in “Non- inherited antibiotic resistance,” researchers use mathematical modeling. The mathematical modeling assumes a worst-case scenario where host immunedefenses are inoperative and infection is controlled only by an antibiotic. Two groups are designated to be control group and the variable: replicating bacteria susceptible to antibiotic killing and bacteria with low replication rate which are refractory (resistant) to antibiotics. Even though bacteria are limited to set environmental conditions, they can physically move or be physiologically altered between the two groups in the real world. This mathematical modeling analyses method indicates that the concentration of antibiotics oscillates above and below minimum inhibitory concentration (MIC). Oscillations above and below the MIC allow persistent bacteria to grow as a response to varying antibiotic pressure, but these bacteria are not dynamically readjusting their cell cycles, but rather several bacteria are diversified at different stages of cell growth as a defensive mechanism.
Through these two experiments, scientists can identify two kinds of non-inherited antibiotic resistant bacteria. The first type is a drug-indifferent bacteria. These bacteria do not have the nutrients to metabolize and replicate. Because they cannot metabolize, they cannot internally process the antibiotic that kills them. However, persistent bacteria do have the nutrients to metabolize and replicate, yet they have stopped replicating. Persistence in this context means that the bacteria have the capacity to metabolize and replicate, but do not under certain conditions and therefore become immune to the antibiotics. Since drug-indifferent bacteria cannot metabolize, it is not really a mystery why they are able to survive in the presence of antibiotics. However, what causes the persistent bacteria to stop replicating is unknown. These persistent bacteria have enough nutrients so they should be metabolizing and replicating, but they have stopped for reasons unknown.
Levin and Rosen also mention that non-inherited antibiotic resistant bacteria may be persistent for reasons related to the in vitro environment of the host. The first reason is that the polysaccharide matrices that make up the biofilms allow less access to the antibiotics. Therefore, in actual physical bodies, bacteria may simply not be exposed to enough antibiotics to kill them. Furthermore, the lack of nutrients in biofilms do not allow the bacteria to replicate. Finally, the least supported reason is that bacteria in biofilms enter a completely different stage unrelated to the stationary phase of growth or lack of nutrients.
In conclusion, researchers should consider doing more studies on the role of non-inherited antibiotic resistance. For current patients, there are so many factors inside the host that can affect the outcome of an infection that it is difficult to figure out the role of non-inherited antibiotic resistance as a part of antibiotic treatment. Likely a combination of mathematical models, computer simulations, and animal testing mixed with pharmacology studies will be needed to come up with a empirical and rational approach to antibiotic treatment in the future.
Balaban, Nathalie Q., Jack Merrin, Remy Chait, Lukasz Kowalik, and Stanislas Leibler. “Bacterial Persistence as a Phenotypic Switch.” Science 305.5690 (2004): 1622- 625.
Levin, Bruce R., and Daniel E. Rozen. “Non-inherited Antibiotic Resistance.” Nat Rev Micro 4.7 (2006): 556-62.