Addressing the Global Crisis of Antimicrobial Resistance (AMR)
Antimicrobial resistance (AMR) occurs when bacteria, viruses, fungi and parasites evolve to resist the effect of antimicrobial drugs designed to kill them. If left unresolved, the world faces a grim outlook; the World Health Organization has declared AMR as one of the top 10 global public health threats facing humanity and estimates that 10 million deaths could be caused by drug-resistant diseases each year by 2050.
SMART’s AMR interdisciplinary research group (IRG) is committed to addressing this global health crisis by developing innovative and groundbreaking solutions.
Innovative and novel approaches to combating AMR infections
In 2023, AMR achieved several significant milestones, including several groundbreaking discoveries.
A confocal microscopy image of macrophages treated with MTX (cyan) that have eaten bacteria (magenta)
VRE is a highly resilient bacterium notorious for causing severe bloodstream infections, urinary tract infections, and wounds associated with catheters and surgical procedures. Over time, it has developed antibiotic resistance, making treating VRE infections a formidable challenge. Most notably, VRE has shown resistance to vancomycin, a widely used antibiotic for treating Gram-positive bacterial infections.
We've pioneered an innovative treatment approach that pairs mitoxantrone (MTX), a well-known anticancer agent, with vancomycin, a commonly used antibiotic, to combat VRE infections. This novel therapy effectively addresses VRE and strengthens the immune system's ability to fend off bacteria. It achieves this by luring more immune cells to the infection site, enhancing their bacteria-fighting capabilities, and promoting the healing of wounds.
Due to its intrinsic and acquired resistance to numerous standard antibiotics, including vancomycin, the available treatment options for VRE infections are exceedingly limited. Hence, the team's groundbreaking discovery of MTX and vancomycin as a highly effective dual therapy, capable of targeting both the bacterium and the host, marks a significant advancement in the battle against VRE infections.
SMART AMR researchers Peiying Ho, Sharon Ling, Boon Chong Goh, and Patrina Chua (from left to right) performed compound screening to identify novel antibiotic combinations.
Mycobacterium abscessus (M. abscessus) is a non-tuberculous mycobacterium (NTM) responsible for chronic lung-related infections. This bacterium is widespread and resilient, displaying resistance to commonly used antibiotics and presenting considerable obstacles in current treatments.
SMART AMR has discovered a novel therapy combining clarithromycin and rifaximin, where the latter acts as a clarithromycin potentiator with the ability to increase clarithromycin sensitivity and improve its ability to kill M. abscessus. Our researchers have displayed how rifaximin and clarithromycin show efficacy both in vitro and in a zebrafish embryo infection model. This pioneering development holds great promise for surmounting the challenges associated with NTM infections.
The team’s next step entails conducting preclinical studies to evaluate the therapy's effectiveness against M. abscessus. Additionally, we are partnering with a commercial partner to develop inhalation formulations designed for direct lung delivery, paving the way for upcoming human clinical trials.
(L to R) SMART researchers Dr Cui Liang, Dr Lee Wei Lin, Dr Ho Peiying, and Principal Investigator Prof Peter Dedon used a sophisticated mass spectrometry technology developed at SMART and MIT to understand how bacteria cells adapt and survive antibiotics
Amid the global AMR pandemic, it is paramount to understand the adaptive strategies employed by bacteria as they evolve in response to stressors.
SMART AMR researchers have discovered a new stress signalling system that enables bacteria cells to adapt and protect themselves against the immune system and certain antibiotics. In E. faecalis, a common bacterium found in the human gut, an enzyme known as RlmN has been observed to actively sense chemical and environmental stressors and rapidly trigger the production of other proteins that allow the bacterium to adapt and survive.
Deciphering these cellular adaptation and survival mechanisms opens the door to developing drugs that can thwart the adaptive response, ensuring that pathogens maintain their sensitivity to antibiotics.
Looking ahead, SMART AMR is committed to further exploring this newfound stress response mechanism and its potential implications for combating drug resistance.
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SMART AMR, alongside our collaborators, will continue furthering studies in this field to contribute to the collective global fight against AMR. Through research and diagnostics into the resistance mechanisms of bacteria and the development of novel technologies that can help address these issues, we look forward to paving the way for a healthier world for future generations.