A two-pronged approach to antibiotic resistance


Breaking down the microbiology world one bite at a time

A two-pronged approach to antibiotic resistance.

Antibiotics are a type of medication we all have used at one point or another in our lives. Ever since Alexander Fleming discovered the first antibiotic, penicillin, in 1928 and paved the way for the subsequent antibiotic discovery era, these compounds revolutionized the field of medicine. While infectious diseases and plagues topped the charts of mortality rates in the past, with the help of antibiotics, those ranks have now been distributed to non-communicable diseases such as cardiovascular diseases. But that does not mean that we will never need to worry about the consequences of a pre-antibiotic era again.

As the scientific and medical community has made progress in identifying ways to tackle bacterial pathogens, these pathogens have also acquired different strategies for escaping the negative effects of the antibiotics and developing resistance referred to as antibiotic resistance. This resistance is a result of natural resistance some bacterial species may have and genetic mutations which are propagated to the progeny due to its selective survival advantage among other things. 

Staphylococcus aureus, more commonly known as staph, is a generally harmless bacterial pathogen commonly found on our skin, nose and other parts of the body, but it is capable of causing harm under the right circumstances. In fact, it is the leading cause of skin and soft tissue infections, and can also cause fatal pneumonia, bloodstream, and heart infections. 

igure 1: Scanning electron micrograph of a human neutrophil (blue) ingesting Methicillin-Resistant Staphylococcus aureus (MRSA; purple) Source

S. aureus is increasingly gaining resistance to methicillin, the antibiotic used as a first line of defense for this pathogen. This is forcing physicians to turn to last-resort antibiotics after which there are no alternative treatments for resistant bacteria. In addition to developing antibiotic resistance, methicillin resistant Staphylococcus aureus (MRSA) also has mechanisms to hide from the first-responder cells of our immune system like neutrophils, which then fail to adequately protect us from this pathogen. Together, both of these properties of MRSA make it extremely difficult to treat these infections and consequently lead to often fatal consequences. This highlights the medical urgency of developing novel therapeutics or therapeutic strategies to tackle multi-drug resistant bacteria.

A novel approach currently being explored to tackle this problem is the development and use of immunotherapeutics which take inspiration from our body’s own antibacterial strategies and enhance our immune response. For instance, our immune system produces host defense peptides (HDPs) which can both directly kill/inactivate the pathogens and create a chemical gradient around them to recruit other immune cells to tackle the infection. Thereby, this strategy could potentially be a solution for MRSA which both hides from the immune system and is resistant to many of the currently available antibiotics. 

Intrigued by these natural molecules, Payne et al. (2021) proposed the creation of an artificial version of HDPs to treat MRSA. They suggested doing this by chemically linking/combining an immune-activating compound (which can create a chemical gradient to attract immune cells to the site of MRSA infection) to a bacteria-targeting compound (which will specifically bind to MRSA and kill it). This compound combination would allow the immune system to specifically detect and attack the invading MRSA bacteria (Figure 2a). 

For their immune-activating chemotactic, they chose formylated peptides (fPeps) which are small molecules well-known for binding to and activating neutrophils, consequently promoting their recruitment at infection site and phagocytosis (ingestion, digestion using antibacterial mechanisms, followed by neutrophil death) of the bacteria. They possess this incredible ability as in nature fPeps are a ubiquitous component of bacterial proteins and so our immune system has learnt to recognize and initiate an immune response in their presence. For their bacteria-targeting compound, they chose the antibiotic vancomycin which is well-known for binding to and destroying the cell wall of S. aureus

Figure 2: Two-pronged mechanism of host defense peptides to directly kill bacteria and stimulate immune cells that can kill the bacteria. (a) Mechanism of host-defense peptides found in nature. (b) Mechanism of antibiotic-chemoattractant immunotherapeutic. Figure created using Biorender.com.

Artificially combining the two compounds then generates an incredible immunotherapeutic which binds directly to S. aureus cells, while creating a chemoattractant gradient around the infection site to promote neutrophil recruitment and killing of MRSA (Figure 2b). So far, Payne et al. (2021) have demonstrated the impressive success of this immunotherapeutic in test-tube/ petri dish models of MRSA infection (outside organisms) and in mice with MRSA pneumonia. This shows great promise for this new approach and brings us a step closer to being able to have a solution for MRSA infections in humans. 

While this is exciting news, it should be noted that there is still a long road of research ahead before determining if this strategy could be used clinically in humans. However, this research still demonstrates an exciting and promising new avenue for tackling antibiotic resistance. 

Link to the original post: Payne, J.A.E., Tailhades, J., Ellett, F. et al. Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus. Nat Commun 12, 6157 (2021).

Other references:

Association for Professionals in Infection Control and Epidemiology. (2019, June 27). Staphylococcus aureus. APIC. https://apic.org/monthly_alerts/staphylococcus-aureus/

Ventola C. L. (2015). The antibiotic resistance crisis: part 1: causes and threats. P & T : a peer-reviewed journal for formulary management, 40(4), 277–283.

Wen, X., Xu, X., Sun, W., Chen, K., Pan, M., Wang, J. M., Bolland, S. M., & Jin, T. (2019). G-protein–coupled formyl peptide receptors play a dual role in neutrophil chemotaxis and bacterial phagocytosis. Molecular Biology of the Cell, 30(3), 346–356. https://doi.org/10.1091/mbc.e18-06-0358 

Guerra, F. E., Borgogna, T. R., Patel, D. M., Sward, E. W., & Voyich, J. M. (2017). Epic immune battles of history: Neutrophils vs. Staphylococcus aureus. Frontiers in Cellular and Infection Microbiology, 7. https://doi.org/10.3389/fcimb.2017.00286 

BioRender. (n.d.). https://app.biorender.com

Featured image: Scanning electron micrograph of a human neutrophil ingesting Methicillin-Resistant Staphylococcus aureus (MRSA; purple). Link here