Promising Innovations To Bend The AMR Curve (Part-I)
The emergent global threat of Antimicrobial Resistance (AMR) is in need of innovative ways to contain and control what is set to be the next epidemic. This requires combined multi-sectoral co-operation on different fronts. Scientific innovations have the potential to control AMR at source, either by early detection and identification of the pathogen, or by differential therapeutic approaches that offer alternatives to existing antimicrobials, and can also prevent development of microbial resistance. There are many noteworthy solutions in this domain of which CARB-X supported innovations by Module Innovations, Bugworks Research and Gangagen Biotechnologies stand out prominently from India.
Addressing unmet needs
Module Innovations is addressing Urinary Tract Infections (UTIs) that constitutes the second highest infection in the human body affecting nearly 150 million people globally. It has been reported that 70% of cases of antibiotic prescriptions are empirical and in 30% of cases antibiotics are given unnecessarily as it was not needed. Due to lack of availability of affordable, rapid and point of care diagnostic methods for bacteriuria (bacteria in urine) and its subsequent antibiotics sensitivity test (AST) profile prompts the caregivers to adopt this route to offer immediate relief to the patient. Module is developing bacteria ID and AST for Uro-pathogens causing UTI. Dr Maya KV, Senior Scientist, Module Innovations adds, “As a female I know UTI’s are extremely common. Empirical pill-popping in UTIs has become a norm. This practice has to change and be supported by evidence to make real progress towards UTI related AMR”. Module’s USENSe, a 15-minute test to identify the bacteria, followed by ASTSENSe, world’s first 2-hour phenotypic test to determine the most effective antibiotic with the MIC aims to address this gap. USENSe is a simple test akin to a pregnancy test, usable by a layman at any kind of healthcare setting, while ASTSENSe is a printer-sized device, operable with minimum training even at the level of a primary care setup. The two tests aim to aid clinicians to reach from empirical to evidence-based therapy. “In clinical decision making, time is of essence. Rapid diagnostics that operate at the point of care will hold the key” emphasizes Dr Sachin Dubey, CEO of Module Innovations.
In therapeutics, Bugworks Research is developing the GYROX series, a new antibiotic family, with a novel mechanism targeting the conserved bacterial targets, Gyrase and topoisomerase, with equal potency. GYROX series is potent against ~10000 superbug clinical isolates from all over the world. The lead molecule in the series, BWC0977, is currently undergoing Phase 1 clinical trial in Australia. It can be formulated as intravenous and oral formulations and is distributed in key organ systems, like lungs, blood, urinary tract etc. The combination of efficacy against resistant strains in mice and rat models of infection (thigh, lung and UTI), intravenous and oral dosage forms with pan-organ bioavailability makes it the preferred treatment in critical care, hospital and the community settings. “India is unfortunately the epicentre of antimicrobial resistance, we hope to deliver the solution for this global unmet need from India” reiterated Dr Santanu Datta, CSO of Bugworks. These characteristics have not been seen in a novel class of antibiotics since the fluoroquinolones which were discovered over 60 years ago and are being rendered useless due to alarming rates of resistance.
Also, in the therapeutics domain, GangaGen Biotechnologies is designing and developing protein as precision antibacterial agents to treat drug-resistant bacterial infections. This is to address the increasing resistance of gram-negative bacteria to multiple classes of antibiotics resulting in multi-drug resistance (MDR). Among these bacteria, E. coli and Klebsiella pneumoniae are most important since they cause serious blood stream infections, urinary tract infections and pneumonia. Widespread MDR combined with the lack of novel antibacterials in the development pipeline exacerbates this critical situation and hence highest priority needs to be given to novel molecule discovery to tackle this problem.
In the CARB-X funded project, GangaGen is developing natural and engineered klebicins to specifically target Klebsiella pneumoniae. Klebicins are narrow-spectrum agents with novel mechanism of action that enable killing of target pathogen without impacting the normal microbiome. Klebicins are potent antibacterial molecules and GangaGen has demonstrated its in vivo efficacy in relevant animal models of infection. They now hope to develop these novel molecules that will add to the arsenal for targeting highly drug-resistant bacteria.
Challenging the status quo and way forward:
Module Innovation hopes to bring down the average time of 3 days that is currently required for culture and sensitivity test so that evidence-based treatment can be initiation faster. They are challenging this status quo with USENSe and ASTSENSe that give the same information in a little over 2 hours. For clinical decision making and for bringing a positive impact this fast turnaround will be of essence. The rapid assay that can be used at the lowest level of healthcare infrastructure can thus complement and integrate well within the present clinical pathways.
Bugworks relative breakthrough in an area that had not seen much success for the last 60 years has been noteworthy. Aside from the varied skill sets of the team, Bugworks attributes its success to their distributed model of “innovation within and execution outside”. About 90–95% of their data is generated from vendors and partners around the globe It is generally believed that about 50% of the data from the best labs in drug discovery is not reproducible, and nearly 28 billion USD is spent in attempting irreproducibility of biomedical research in the US! Bugworks was quick to learn that these failures are mainly because of intrinsic variance and sub-conscious bias in conducting and interpreting biology experiments. It is for this reason, their different data-sets that add up to the whole story are generated by different organizations spread across the world. This eliminates to a very large extent the sub-conscious bias in interpreting the data and arriving at conclusions, thereby yielding highly robust and reproducible data packages. Interestingly for the entire BWC0977 data package submitted for regulatory approval, the in-house generated data constituted only about 1–2% of the total data! They attribute this distributed model to be a key determinant of their success.
The success of the three innovations so far has been due to a mix of scientific and execution acumen, while being supported by the best in the ecosystem. Evidence-based scientific and technical grounding, enabled alongside monitoring the pulse of the AMR market, while leveraging the collective expertise of their respective partner and vendor networks has stood them in good stead.
In the second, and concluding part of the blog, the three companies will share their views on how their innovations can be stepped up in the fight against AMR.
Disclaimer: The blog is a compilation of information on a given topic that is drawn from credible sources; however this does not claim to be an exhaustive document on the subject. It is not intended to be prescriptive, nor does it represent the opinion of C-CAMP or its partners. The blog is intended to encourage discussion on an important topic that may be of interest to the larger community and stakeholders in associated domains.