Addressing the Threat of Antimicrobial Resistance
The antibiotic era began with the 1946 introduction of penicillin, a drug that many saw as a “silver bullet” with which infectious disease could be eradicated. Unfortunately, it quickly became clear that antibiotics and antimicrobial resistance (AMR) went hand-in-hand, as four penicillin-resistant bacterial strains were isolated from patients within the first year of introduction.1
In the following decades, multiple classes and generations of antibiotics and other antimicrobials were discovered and developed. Following close behind were new modes of AMR: a near real-time demonstration of adaptation and evolution, albeit an unfortunate one. Now, resistance has transformed into a global threat; a recent study directly attributed 1.27 million deaths globally to bacterial AMR, contributing to a total of 4.95 million bacterial AMR-associated deaths worldwide in 2019 alone.2
In vivo imaging sheds light on novel antibiotics and immune mechanisms
One of the primary pathogens responsible for these bacterial AMR-attributed and associated deaths, Staphylococcus aureus, has been a focus of Prof. Nathan Archer and his research group at Johns Hopkins University. As the primary cause of skin and soft tissue infections in humans and the second-leading cause of death associated with AMR, S. aureus is a prevalent and deadly pathogen for which novel therapies are desperately needed. Prof. Archer’s group has been using innovative mouse models of S. aureus infection coupled with in vivo imaging to evaluate potential therapies and study the immune responses of hosts.
One of their projects focuses on a novel antibiotic TBI-223, Prof. Archer’s group utilized a bioluminescent strain of methicillin-resistant S. aureus (MRSA) to generate mouse models of MRSA skin infection. After in vivo imaging, quantification of the bioluminescent signal showed that TBI-223 significantly reduced bacterial burden, suggesting that this novel antibiotic is effective at treating S. aureus skin infections. Prof. Archer’s group also used the bioluminescent MRSA in concert with models of orthopedic implant-associated infections to show that high-dose rifampin therapy can shorten antibiotic course, and that antibiotic-coated implants had much lower microbial burden than non-coated implants.
Prof. Archer’s group has additionally leveraged in vivo imaging to investigate immune responses to S. aureus; they recently identified IL-17-producing eosinophils as key drivers of inflammation in atopic dermatitis, and elucidated the role of neutrophils in driving inflammation in psoriasis.
High-Content Screening provides deep bacterial phenotyping
While in vivo bioluminescent and fluorescent imaging has proven to be a powerful tool, it remains one of multiple imaging modalities being used to study AMR and address multidrug resistance (MDR). Prof. Stephen Baker of the University of Cambridge has been using high-content screening (HCS) to study bacterial populations in great detail. One of the species his team focuses on is Salmonella typhi, the typhoid fever-causing microbe that is becoming increasingly MDR. Using HCS, Prof. Baker’s group recently examined how ciprofloxacin affected the morphology of S. typhi over the course of 24 hours. The data gathered enabled them to show that bacterial morphology can be predictive of pathogen response to antimicrobial exposure. With the help of machine learning, Prof. Baker’s group predicted whether a pathogen would be susceptible or resistant to an antimicrobial with 92% sensitivity, all while never exposing the bacteria to the drug.
The growing threat and increasing lethality of AMR necessitate the development of novel models, assays, and technologies in order to produce the next generation of antimicrobial therapies.
In the webinar below, professors Archer and Baker discuss in more detail how they are using in vivo imaging and High-Content Screening to address this problem.
1. Rammelkamp, C.H.; Maxon, T. Resistance of Staphylococcus aureus to the Action of Penicillin. Proc. Soc. Exp. Biol. Med. 1942, 51(3), 386-389. doi:10.3181/00379727-51-13986
2. Murray, C.J.L., et al. Global Burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022, 399, 629-655. doi: 10.1016/S0140-6736(21)02724-0