Malacidins: the answer to antibiotics resistance?

New Staphylococcus aureus strains are causing severe skin infections that are difficult to overcome with traditional antibiotics. Malacidins, an antibiotic discovered in dirt, may be the solution to cure skin infections and combat antibiotic resistance. Is the arms of antibiotics race finally coming to an end?

Antibiotics are used to fight bacteria and cure infections. Every infection can be caused by a different bacterium that is treated with different antibiotics. There is an exhaustive list of antibiotics; some common ones are amoxicillin, penicillin, and ampicillin which are used to treat infections caused by specific bacteria. However, infectious diseases seem to be one of the leading causes of death all over the world. Frequently, bacteria become resistant to antibiotic treatment after consistent exposure, thus lowering our ability to effectively treat infections.

Antibiotic resistance is one of the greatest threats to humanity, with many infections being left untreated. Hover et al. (2018) took a new approach and decided to look beyond cultured bacteria and into the realms of nature. Lo and behold, they found the mighty powerful malacidins through a culture-independent process that entailed thorough DNA sequencing, bioinformatic analysis, and biochemistry. Will malacidins hold the power to combat antibiotic resistance or play into the arms race that has always been?

Modified from MeMed.

Antibiotic resistance is a growing problem with infections being left untreated because bacteria gain resistance to the drug used to fight them. Antibiotics kill the majority of bacteria, leaving behind a few that survive and multiply. The resistance of the drug can be transferred to other bacteria causing an increase in antibiotic resistance. Malacidins are antibiotics that work to overcome antibiotic resistance by their ability to kill several multidrug-resistant bacteria. This helps to alleviate problems that arise when bacteria become resistant to the drug.

Hover et al. found that malacidins are able to treat infections caused by gram-positive bacteria like Staphylococcus aureus, that have a thick bacterial cell wall. Malacidins also work against many pathogens that are resistant to multiple drugs, showing its capability to be an effective antibiotic to fight infections. For example, strains of methicillin-resistant Staphylococcus aureus (MRSA) are resistant to the majority of antibiotics, making it hard to treat the infection.  Applying malacidins on rat wounds was successful in sterilizing them. Even if MRSA is resistant to almost all antibiotics, the incredible antibacterial quality of malacidins was able to work by disrupting the cell wall of bacteria, eventually killing them.

Adapted from Hover et al. (2018).

In vivo, an animal wound model was used to look at the efficacy of malacidins on skin infections with S. aureus. Malacidin was applied topically to the infected wounds to see how it worked. a) At 24 and 72 hours post-infection, malacidin A treatment showed no CFU (colony forming unit, the active microorganisms in the wound), indicating no bacterial burden and effectiveness in treatment against S. aureus infections. Meanwhile, the control treatment (vehicle) indicated the formation of active microorganisms. Thus, malacidin A is successful in treating S. aureus skin infections in animal wound models. b) When malacidins were compared to the controls, the fold change in MIC (minimum inhibitory concentration) was lower, showing its capacity to inhibit the growth of S. aureus at low concentrations and effectiveness as an antibiotic agent. After 20 days of continuous exposure to malacidin A,  S. aureus did not develop any resistance.

The mode of action of malacidins is dependent on calcium to break the cell wall of bacteria. Its action is different from previously known calcium-dependent antibiotics which commonly depolarize the membranes. On the contrary, malacidins work by binding to a precursor of the cell wall, lipid II, which helps create the bacterial cell wall. Like a mastermind at work, malacidin prevents the incorporation of lipid II, which disrupts the synthesis of the bacterial cell wall and can lead to cell death. Maybe malacidins truly have taken a lead in this arms race between bacteria and antibiotics.

With more than 1.2 million deaths worldwide in 2019, researchers are looking for more variants of malacidins and other antibiotics in the dirt that may be helpful in combating antibiotic resistance. However, much more research is needed before malacidins can be used for medicine. The discovery of malacidins is astonishing in its ability to someday address a huge health crisis of ineffective antibiotics against pathogens that cause harmful infections and diseases.

Learn more about malacidins
  1. FDA’s attempt at overcoming antibiotic resistance
  2. Deploying artificial genes to overcome antibiotics resistance (Youtube video)

About the Author

Rubab Shafiq is a fifth-year undergraduate student pursuing a double major in Human Biology and Psychology with a minor in Health Humanities at the University of Toronto. She hopes to get more involved in research surrounding the concepts of genomics. She loves to travel and is always on the lookout for a new trail to walk.

References

Hover, B et al. (2018). Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nature Microbiology, 3, 415–422. https://doi.org/10.1038/s41564-018-0110-1

Antibiotic resistance crisis. MeMed. (n.d.). Retrieved April 20, 2022, from https://www.me-med.com/the-resistant-bacteria-problem

Institute for Health Metrics and Evaluation. 2022. The Lancet: An estimated 1.2 million people died in 2019 from antibiotic-resistant bacterial infections, more deaths than HIV/AIDS or malaria.

Featured image Dylan de Jong on Unsplash (license).

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