Just as the research community succeeds in developing a new antibiotic to deal with bacteria, the bacteria, after a period of time, form a resistance to the drug, resembling a "cat and mouse" game between the two parties.
However, an international research team led by researchers from Texas A&M University in the United States is one step away from deciding the outcome of that game in favor of the patient, thanks to a new family of polymers that target the membrane of these microorganisms, leading to the killing of bacteria without causing drug resistance.
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Antibiotic-resistant bacteria are becoming an increasing public health hazard, directly causing the death of 1.27 million cases each year, in addition to indirectly causing 4.95 million deaths, according to a study published on November 21, 2023, in the renowned journal The Lancet.
Bacteria form resistance to antibiotics in several ways, which are:
- Target Modification: Bacteria mutate their genetic material, leading to changes in the target site where the antibiotic typically binds to and disrupts cellular processes. This change prevents the antibiotic from effectively interacting with the intended target, rendering it ineffective.
- Efflux Pumps: Some bacteria develop specialized proteins known as efflux pumps that effectively pump antibiotics out of the bacterial cell, reducing the drug's concentration inside the cell and diminishing its effect.
- Gene Transfer: Bacteria can transfer genetic material—including genes that confer resistance to antibiotics—to other bacteria through mechanisms such as conjugation, allowing these resistant genes to spread rapidly among bacterial groups.
- Enzymatic Degradation: Bacteria can produce enzymes that chemically modify or destroy antibiotics before they can exert their effects. For example, beta-lactamase enzymes break down penicillin-type antibiotics, making them ineffective.
- Biofilm Formation: Bacteria can form protective biofilms that act as shields against antibiotics, making it difficult for drugs to penetrate bacterial cells and reach their targets.
- Dormancy or Slow Growth: Bacteria can enter a state of dormancy or slow growth, making them less susceptible to antibiotics, as the drugs are more effective against actively dividing cells.
Targeting the Bacterial Membrane: A Guaranteed Mechanism
Targeting the bacterial membrane using certain polymers is effective against bacteria and reduces the possibility of antibiotic resistance for several reasons:
- Physical Disruption: The polymers work by physically disrupting the bacterial cell membrane rather than targeting specific internal processes or molecules within the bacteria as traditional antibiotics do.
- Non-Specific Interaction: Polymers interact with the lipid membranes that coat bacterial cells, causing damage to the structural integrity. This disruption leads to the leakage of cellular contents and ultimately cell death.
- Complex Nature: The bacterial membrane is a crucial and complex structure for bacterial survival. Targeting this structure with polymers affects multiple aspects of the cell rather than a single specific target, making it difficult for bacteria to develop resistance.
- Low Mutation Rate: The membrane disruption mechanism does not inherently lead to a high rate of bacterial mutation as traditional antibiotics do. Mutations in target sites for antibiotics often lead to resistance. However, altering the membrane in a way that overcomes the action of these polymers is more complex and less likely to happen quickly.
Despite polymers showing effectiveness in deciding the "cat and mouse" game between drugs and bacteria, a common problem has so far prevented their use in drug production. Researchers in the new study published by the journal Proceedings of the National Academy of Sciences claim to have overcome this issue.
The common approach to manufacturing drug-use polymers relies on "step-growth polymerization," which limits precise control in their design to allow selectivity. This selectivity differentiates between bacteria and human cells when targeting the cell membrane—a problem the researchers solved by designing polymers in a new way.
"Step-growth polymerization" is a method of producing polymers by joining monomers (the basic unit of polymers) through condensation reactions, often involving the removal of small molecules such as water or alcohol or hydrogen chloride. The process begins with monomer activation, typically through heating or the presence of a catalyst. Then, the activated monomers react with each other, forming covalent bonds between their functional groups, with the removal of small molecules as byproducts. Polymer chains continue to grow as more monomers interact, until the desired chain length is achieved.
However, a major drawback of this method is "lack of control," as it often lacks precise control over chain length, leading to a wide molecular weight distribution and variations in polymer properties—which the researchers addressed using "controlled radical polymerization."
"Controlled radical polymerization" refers to a set of techniques used in polymer chemistry for the precise control of polymer chain growth, resulting in types with well-defined structures, controllable molecular weights, and specific functionalities.
Greater Efficacy: A New Polymer
If we imagine the process of building polymer chains as "building a toy train with special blocks," then using "controlled radical polymerization," the researchers created a new type of train track by designing a special building block that can be easily linked together several times to create a long track. Each block has a special charge that attracts each other like magnets, making the whole track of one type of charge. A unique and new catalyst called "AquMet" – which resembles magic glue – was used to stick these blocks together.
Quentin Michaudel, Assistant Professor in the Department of Chemistry at Texas A&M University, states in a press release published on the university's website, "This glue is very important because it withstands a high concentration of charges, and it's soluble in water, which is an advantage that's not common in this type of operation."
Michaudel and his research team tested the new polymer against two main types of antibiotic-resistant bacteria, "Escherichia coli" and "Staphylococcus aureus," and proved its effectiveness in targeting them. They also tested the polymer's toxicity against human red blood cells, yielding very encouraging results.
The research team now aims to enhance the activity of these polymers against bacteria while improving their selectivity for bacterial cells. They are currently assembling different versions of polymers to achieve these goals and plan to conduct in vivo experiments in the near future.
Long-Term Testing
Meanwhile, Mohamed Mansour, a professor at the College of Pharmacy at Beni Suef University in Egypt, lauds the achievements of this study on a laboratory scale. However, he emphasizes that the new polymer requires long-term testing to ensure that bacteria do not develop resistance against it.
Mansour tells Al Jazeera Net that "verifying this fact requires long-term tests to confirm that resistance will not develop over time. Also, we need to ensure the accuracy of the polymers in distinguishing between bacterial and human cells, which will also take a long time to prove."
He adds, "If these two matters are settled, we will be facing an important breakthrough in ending the ongoing battle between drugs and bacteria."
