by Nithya Ramcharan
Antibiotics have for long been a prominent facet of medicine and are ubiquitous in households today due to their accessibility. At the earliest sign of a bacterial infection, we consume antibiotics with the confidence that it will be eradicated within a couple of weeks. However, this confidence has led to antibiotic abuse, a major issue in the medical field currently. For one, overusing antibiotics depletes the natural fauna populating certain organs like our intestines, making them more vulnerable to virulent bacterial strains. Naturally-occurring bacteria in our organs are a component of the immune system’s first line of defense and play a crucial role in immune system homeostasis and development [1]. Most importantly, antibiotic abuse has led to what some sources dub “the Antibiotic Resistance Crisis.” Antibiotics are often overprescribed when many of the infections’ pathogens are left unidentified, so out of caution, infections are assumed to be bacterial. 80% of antibiotics sold in the US are funneled into livestock for growth and prophylaxis [2]. As a result, bacteria are rapidly developing resistance to many commercial antibiotics and are returning more potent than ever. Bacterial genes can be transferred both to relatives and non-relatives through plasmids, circular DNA molecules in bacteria that can replicate independently of their host bacterial cell. This can confer resistance rapidly not only within a single population but also between different bacterial species [3]. Researchers are thus looking for alternatives to antibiotics to curb bacterial resistance and its catastrophic consequences.
One solution researchers have identified is a group of proteins occurring naturally within our bodies. Known as “antimicrobial peptides” (AMPs), these proteins are small, positively charged molecules that function within organisms as a natural immune response against microbes. Most commonly, AMPs can kill a bacterial cell through lysis; interactions between the positively charged clusters of an AMP and the negative charges in the phospholipid bilayer of a bacterium’s cell membrane form pores in the membrane, which ruptures the bacterium [4]. AMPs can also inhibit bacterial growth by targeting intracellular operations after permeating the membrane. They are present in organs in the human body most susceptible to infection such as the skin and the eyes [4]. Crucially, unlike antibiotics, bacteria have not developed solid resistance to AMPs, which is a key reason why AMPs offer a more attractive and effective method of treating bacterial infections. However, there is still little established research on how exactly AMPs neutralize bacteria.
Professor Anatoly Kolomeisky of Rice University’s Department of Chemistry has been investigating the mechanisms of AMPs. His work started with the observation that antibiotic abuse can be attributed to people wanting to completely eliminate bacteria from their systems. His team developed a theoretical framework based on preexisting quantitative data to analyze how AMPs kill bacteria by considering bacterial growth as well as AMP entrance and inhibition rates into the bacteria as stochastic (randomly determined) processes. The model, in essence, consisted of a set of chemical reactions that would eventually lead to elimination of bacteria from the system. “We looked at the system as a sequence of states,” said Dr. Kolomeisky. “These states differed from each other only in the amount of AMPs.” In the occasion that the AMPs kill the bacterial cell, the corresponding state is removed. He called the model a “one-dimensional picture in a chemical space,” in the sense that it provided more of a black-or-white outlook: with certain factors, all the bacteria would either be killed or none of them would be killed. Although the model is simplified and every biophysical process is not accounted for, the model offers a convenient method for calculating the dynamics of the reaction, such as bacterial growth rate and bacterial clearance rate and the parameters that can modify these rates. Additionally, unlike other theoretical research on AMPs, this study takes into account the stochasticity of the processes of AMPs entering and inhibiting the cell [5]. This offers an effective means to further understand the mechanisms of AMPs that can be analyzed statistically and later compared with empirical data.
Using the model, the team found out that the probability of inhibition and bacteria clearance rate have a positive relationship. Additionally, both processes of AMP entrance and inhibition of bacteria are equally important for AMPs to suppress bacterial growth. One finding is that higher heterogeneity in the AMPs facilitate faster entrance rates, while faster inhibition rates lead to lower heterogeneity among the types of AMPs. Controlling the heterogeneity in AMPs is key to balancing entrance and inhibition rates and thus achieving an optimal bacterial clearance rate [5]. Even though the stochastic model is simplified to fit the available information, the mean inhibition times predicted by the model are consistent with those observed in other studies [5].
Once these properties are understood, the applications of AMPs are numerous. They expand beyond inhibiting just bacteria and could suppress other pathogens. They can potentially be used in regulating cell division, facilitating wound healing, assisting in surgical healing, and suppressing cancer cells. AMPs activated by environmental factors such as pH have been developed for drug therapy. LL-37, an AMP found in humans, is one example of an AMP currently in commercial use. It has been identified to have bactericidal, anti-cancer, and anti-inflammatory properties [7]. Aside from medicine, they can be used in food production as natural food preservatives. One of them, pedocin PA-1 (produced by a diplococcus, a type of round-shaped bacterium), is used as a food preservative to prevent meat deterioration [6]. AMPs have also been identified as potential animal feed components to boost health and immunity in animal farming and aquaculture. AMPs with antifungal properties could be used as pesticides in the agriculture industry.
However, much is left to discover about AMPs, as they are a diverse group of peptides that work differently depending on their environment; for example, some operate at the millimolar scale, while some require nanomolar concentrations to function. In addition, knowing how to optimize the entrance and killing rates is important in determining the ideal level of heterogeneity among the AMPs attacking the cell. Dr. Kolomeisky is advancing his current research on AMPs by investigating how using more than one type of AMP affects bacterial clearance. Implementing a “cocktail” mix, as he called it, of AMPs would kill bacteria more efficiently. Even though the rate of the reaction decreases as more types of AMPs are introduced, the probability of killing bacteria increases. He is also researching the dynamics of cancer development and cell cycle regulation, and could combine his research with AMPs to help better understand both processes.
Once the mechanisms of AMPs are better known, they can revolutionize biomedicine. They can replace antibiotics in many medical treatments, thus mitigating the Antibiotic Resistance Crisis yet still allowing antibiotics to be used when needed. Reducing unnecessary usage of antibiotics will insulate them from the imminent threat of resistance developing in bacteria so rapidly. Beyond medicine, AMPs serve as better alternatives for inorganic chemicals used in food preservatives, growth promoters, and pesticides as they are naturally-occurring molecules that might be less likely to harm the organisms they aren’t programmed to target. In the nature of an archetypal journey of self-discovery, the solution to the antibiotic resistance crisis lay within us this whole time.