A peek behind the paper – Shilian Xu on the dominance of different bacterial genotypes under sublethal antibiotic pressure

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Take a look behind the science of a recent Future Microbiology article, entitled: “The dominance of bacterial genotypes leads to susceptibility variations under sublethal antibiotic pressure”, as we ask author, Shilian Xu (Monash University, Melbourne, Australia), about the rationale behind this research and his hopes for the future.

What inspired you to conduct this research?

Mathematically, the main research aim of nonlinear dynamical system – particularly ordinary differential equation, delayed differential equation and difference equations is to study the long-term behaviors of systems with the evolution of time, particularly equilibria, periodical cycle and even chaos.

Biologically, bacterial resistance under sublethal bactericide pressure also evolves with respect to time, coinciding with the main research focus of nonlinear dynamical system. Moreover, by introducing the average killing rate of the bacterial population, the collective resistance of the bacteria population is equivalent to the stability of equilibria or periodic cycles in the proposed model employed by nonlinear dynamical system.

In addition, the mathematical models describing the bacterial resistance under sublethal bactericides also provide a new task for the mathematical research. In fact, existing mathematical models and their analysis of bacterial resistance heavily depend on the numerical simulation of the given set of parameters and its combinations. Because of measure error of parameters, the theoretical results and their biological interpretations may not be representative.

However, due to a non-necessity to provide an analytical solution or closed-form solutions, the qualitative analysis and bifurcation analysis of nonlinear dynamical system provides all possible dynamical behaviors of the system with variations of parameters. By employing the qualitative analysis and bifurcation analysis, we found that for the homogenous and heterogenous bacterial populations under the sublethal bactericide pressure, bistability exists between survival and eradication of the bacterial populations. Thus, it indicates that the susceptibility variation of the bacterial population to bactericides is the nature of the interaction between bacteria and bactericides.

What were your main findings?

Traditional ideas suggest that occurrence of resistant mutations and acquisition of resistant plasmids lead to susceptibility variation of the bactericides. However, by employing the mathematical model, qualitative analysis and bifurcation analysis of ordinary differential equations, we found that both the homogenous and heterogenous bacterial populations exhibit susceptibility variation to bactericide pressure. Mathematically, for both homogenous and heterogenous bacteria, the switch between survival and eradication of the bacterial population exists under the sublethal bacterial pressure, which is a bistability; biologically, the susceptibility variations of the bacterial population to bactericide pressure is due to the nature of interaction between the bacterial population and bactericides. The possible mechanism of bactericide susceptibility variations is the dominance of different bacterial genotypes under sublethal bactericide pressure, rather than persistence, tolerance or resistance [1].

For the homogeneous bacterial population, the initial bacterial populations determine the switch between survival and eradication of the bacterial populations in the certain bactericide intervals. For the heterogeneous bacterial population, the initial bacterial compositions (both initial bacterial population and proportion) determine the switch among the differential bacterial composition on the long-term evolution in the certain bactericide intervals. These two theoretical results are the first time to be reported. Moreover, they are supposed to be proved by experiments.

Read the article The dominance of bacterial genotypes leads to susceptibility variations under sublethal antibiotic pressure” on Future Microbiology now

Where and how often do bacteria encounter sublethal antibiotic pressure in the environment? Why is this important?

The abuse and unreasonable utilization of antimicrobials for clinical, agricultural and pharmaceutical purposes may lead to a sublethal pressure and environment, which plays an enormous role in resistance occurrence, formation and development. Sublethal bactericide pressure can accelerate horizontal transfer of resistance genes and increased mutagenesis in hypermutator strains [2–4].

Moreover, the sublethal bactericide promotes the specialization of different bacteria genotype in the whole bacterial population. For example, in the E. coli population challenged by the sublethal norfloxacin pressure for 10 days, highly resistant isolates (HRIs) release a signaling molecule, indole, to protect less resistant isolates (LRIs) [5]. For LRIs, the bacteria shield is to sacrifice the large number of LRIs to consume norfloxacin and then to relieve the norfloxacin burden from highly resistant bacteria [6]. Simultaneously, the sublethal bactericide promotes the cooperation among different bacterial genotypes or different specialized bacteria [5,6]. Thus, under the sublethal bactericide pressure, cooperation promotes specialization and specialization allows cooperation, which is known as the positive feedback loop.

How can we prevent bacteria encountering these sublethal concentrations of antibiotic?

We suggest that patients should take the antibiotics according to doctors’ order very strictly. For some resistant pathogens such as Mycobacterium tuberculosis, multiple antibiotic treatments and long-term therapy might be a good choice. Moreover, we should avoid abusing antibiotics as much as possible. In addition, according to our results, if bacteria have presented resistance, increasing the dose of antibiotic might be an effective therapy method.

What work are you hoping to do next in this area?

In heteroresistance some bacteria are susceptible to the bactericides, whereas other bacteria display varying degrees of drug resistance in the bacterial population, a result of bacterial cooperation and specialization lead to heteroresistance.

For the heterogenous bacterial population, we have proved that susceptibility variations of the bacterial population under sublethal bactericide pressure is the nature of interaction between the bacterial population and bactericide by employing the mathematical model of ordinary differential equations. Can we observe the heteroresistance from a completely new perspective?

For the perspective of ‘iterated prisoner’s dilemma’, the best strategy for the HRIs and LRIs is cooperation, which coincides with the experimental data [5]. In fact, this idea also challenges the well-known kin selection theory. The genetic relatedness between HRIs and LRIs are very close, but they cooperate with each other under sublethal norfloxacin pressure.

Additionally, the trend of bacterial specialization and cooperation may be taken into consideration. Lowering the cooperation level among different bacterial genotype may be an innovative way to lower the collective resistance of the bacterial population. Simultaneously, the deterministic models, particularly ordinary differential equations and delayed differential equations, are a promising tool to give a deeper qualitative and quantitative insight of bacterial resistance, particularly heteroresistance.

Read the article now

References

  1. Xu S, Yang J, Yin C and Zhao X, The dominance of bacterial genotypes leads to susceptibility variations under sublethal antibiotic pressure. Future Microbiol. 13,165–185 (2018).
  2. Alekshun MN & Levy SB. Molecular mechanisms of antibacterial multidrug resistance. Cell 128(6), 1037–1050 (2007).
  3. Dan IA & Hughes D. Microbiological effects of sublethal levels of antibiotics. Nat. Rev. Microbiol. 12(7), 465–478 (2014).
  4. Kohanski MA, DePristo MA & Collins JJ. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis, Cell. 37(3), 311–320 (2010).
  5. Lee HH, Molla MN, Cantor CR & Collins JJ. Bacterial charity work leads to population-wide resistance. 467, 82–85 (2010).
  6. Xu S, Yang J, Yin C. Bacterial cooperation leads to heteroresistance. arXiv:1712.08309
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