NextGen antimicrobials: Exploring non-traditional approaches to combat AMR
CRISPR-Cas9, now also a superbug killer
In last few years the CRISPR-Cas9 system has been at the forefront due to its versatility of use in different scientific and medical applications. CRISPR-Cas13a-based antibacterial nucleocapsids (CapsidCas13a(s)) were reported last year for sequence-specific killing of carbapenem-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus by recognizing corresponding antimicrobial resistance (AMR) genes. These constructs that were packaged in bacteriophages can be used as both therapeutic agents against AMR bacterial infections and nonchemical agents to detect bacterial genes for diagnosis.
This is just one of the advancements in the field of non-traditional approaches to combat AMR, a field that had thus far been viewed through the lens of antibiotics-mediated interventions alone.
Why is antibiotic discovery the AMR Achilles Heel?
Antimicrobials have been at the forefront in combating microbial diseases. They have been one of the greatest discoveries in modern medicine. Mid 1900s was perhaps the most rewarding period in antibiotics discovery with over 75% of them being discovered between the 1940s and 1980s and brought into use for medical purposes. Since then however, the pipeline of antibiotics discoveries has dried up with no significant advances. The long timeframe to the market and the uncertain market conditions themselves have led to many bio-pharma and scientists shying away from concerted efforts in this direction. The upsurge of microbes and their variants, due to multiple factors, has contributed to Antimicrobial Resistance (AMR) becoming a global health concern. Many known antibiotics have already lost their effectiveness against these evolving pathogens, with the window between the discovery of antibiotics and the development of resistance against it further narrowing over the decades. It is estimated that at current rates AMR will lower the global GDP by 1 trillion USD, would cause 100 trillion USD in global economic losses and 444 million deaths by 2050.
Approaches, other than the traditional antibiotic-centric methods need to be explored. This is an imperative need not just as treatment alternatives, but also to mitigate the build-up of antibiotic resistance such that the existing antibiotics are effective for longer, and potential new classes of antibiotics, when developed, are not squandered in the near future.
Off the beaten track
While antibiotics have been the preferred traditional approach of combating infections, non-traditional approaches are fast making their presence felt as the next big alternative in the wake of the burgeoning AMR burden worldwide. Although the emergence of bacterial resistance is inevitable due to antibiotic action (drug pressure) and the subsequent evolution of the predominantly resistant variant of the bacteria to escape these effects, measures to minimize and slow-down this emergence and its impact needs to be accelerated and amplified.
Non-traditional antibiotic products have generated considerable interest because of the potential for radically different mechanisms of action that could address unmet needs in AMR.
The mechanism of action of a few of the moieties used in non-traditional approaches are different, and thus gives hope of addressing the problem of resistance.
Antibiotics disrupt essential processes or structures in the bacterial like, cell membrane, cell wall, nucleic acid synthesis etc. Some bacteria can naturally resist certain kinds of antibiotics and in due course become the predominant variant due to survival advantage against the persistent antibiotics pressure, others may acquire resistance due certain gene level changes. However, in stark contrast, the non-antibiotics antimicrobial has a very different mode of action.
· Indirect acting small molecules (virulence, potentiators, BLI combinations etc.):
Small molecule mediated inhibition of bacterial quorum sensing (QS) can control several bacterial virulence factors that cause infections. As these factors are not essential for the bacteria’s survival, it will not generate selective pressure. This reduces the risk of resistance development.
· Direct- and indirect-acting large molecules (peptides, etc.): The antimicrobial peptides (AMPs) can bind and interact with the bacterial cell membranes, leading to cell membrane damage and the eventually resulting in cell death. These AMPs have advantages over the traditional antibiotics with a broad-spectrum of antimicrobial activities including anti-bacteria, anti-fungi, anti-viruses, and anti-cancers, and even overcome bacterial drug-resistance.
· Phage (both wild type & engineered): Direct lysis of target bacteria (scope of action is narrow)
· Microbiome and probiotics: Modification of microbiome to eliminate or prevent carriage of resistant or pathogenic bacteria (breath of action is Narrow to broad)
· Nucleic acid/anti-sense: Anti-sense or target destruction used to interfere with bacterial DNA (scope of action is narrow)
· Drug conjugates (ADC, other dual acting drug conjugates): Antibiotic adjuvants are non-antibiotic compounds that are administered with the antibiotics to either enhancing its activity by blocking resistance, or by boosting the host’s response to infection.
Nurturing non-traditional innovations for AMR
C-CAMP - The Centre for Cellular and Molecular Platforms is one of India’s most exciting Life Science innovation and entrepreneurship ecosystems.
Recognising the need to explore new approaches to treat bacterial infections, C-CAMP conceptualised initiatives under which transformative solutions against AMR are being nurtured.
CARB-X, a global non-profit partnership led by Boston University, is dedicated to accelerating antibacterial research to tackle the global rising threat of drug-resistant bacteria, and has been fostering non-traditional approaches to fight antimicrobial resistance.
Small molecules
The potent small molecule discovered by Dr. Shridhar Narayanan of FNDR, and winner of C-CAMP AMR Quest 2020, has shown activity against a variety of gram positive and gram-negative bacteria. This makes it a formidable component against carbapenem and MDR resistant infections.
CARB-X supports a number of innovative small molecule projects. Antabio is developing Pseudomonas elastase inhibitors that suppress the bacteria’s ability to evade the immune system, whereas HZI HIPS’ indirect-acting Elastase inhibitors suppress the bacteria’s disease-causing ability. Both these innovations identify inhibitors of lasB and are characterized as indirect-acting antibiotics as they do not exert direct bacterial killing.
CARB-X supported BioVersys’ inhibitors target a key regulator of S. aureus toxicity (AgrA); a second project of HZI’s disarm S.aureus’ most important toxin — alpha-hemolysin; and Microbiotix’s inhibitors reverses the host immune system disruption by P. aeruginosa.
Large molecules: Peptides and protein therapeutics
Peptides function over a broad range of pH makes it a suitable antimicrobial candidate.
C-CAMP AMR Quest 2020 winner, Tanay Bhatt from inStem, proposed next-generation peptides like Caspase 8 that could be an arsenal to diminish resistant pathogens. Pepthera Biologicals reverse-engineered antimicrobial peptides to incorporate these in personal hygiene products.
Many CARB-X funded product developers have been working in this domain. In protein therapeutics, Amicrobe’s amicidin-B built for direct application on tissues, finds its application in surgical procedures, trauma, implants. Another innovation in this domain by Contrafect discovered 48 new Gram-negative lysins [bacteriophage-derived enzymes] which exhibit pronounced antibacterial activity when coupled with conventional antibiotics.
Lytica therapeutics generated antimicrobial peptides using their branded Stapling technology which could target MDR Infections. Peptilogics has engineered a broad-spectrum unique peptide-based antibiotic, that finds its application against critical ESKAPE pathogens. Polyphor is designing a new thanatin-derivative antibiotic targeting LPS transport protein A, potent against Enterobacteriaceae.
Biofilm disruption:
CARB-X funded Clarametyx-designed CMTX-101, when combined with antibiotics, destroy biofilms, thereby generating a protective shield covering the ESKAPE pathogens. Trellis, another CARB-X funded product developer, created TRL 1068 integrating nanomaterials with computerized technology. It dissolves biofilm by extracting an essential scaffold protein. Currently they are focused on prosthetic joint infections.
Adjuvants:
C-CAMP AMR Quest winner, Geetika Dhanda of JNCASR, designed membrane-perturbing adjuvants that help overcome the membrane impermeability and over-expression of efflux pumps —
reinforcing the antimicrobial agents, which otherwise would be ineffective on its own.
Bacteriophage:
Multiple CARB-X supported startups are working in this domain. Eligo is transforming bacteriophages to DNA-delivery vectors, using Nobel winning CRISPR technique, that creates strand breaks in resistance genes of resistant bacteria. Similarly, Locus Biosciences CRISPR engineered a bacteriophage cocktail targeting the Klebsiella pneumoniae genome. Phico has created a ground-breaking intravenous engineered bacteriophage drug that delivers as a payload of small acid-soluble spore proteins that inactivate the bacteria’s DNA, with a focus on treating P. aeruginosa-causing ventilator-associated pneumonia. SNIPR Biome’s pioneer SNIPR001 (CRISPR developed) selectively eliminates E. coli infections in the gut of cancer patients.
Immunotherapy:
CARB-X supported Cellics’ revolutionary nano sponge utilizes macrophage cell membranes to absorb bacterial toxins — best applied in synergy with antibiotic treatment. ABX01 by Centauri repurposes existing polyclonal antibodies, thereby addressing hard-to-treat infections by strains: Enterobacteriaceae, A. baumannii, P. aeruginosa. It acts by tethering an epitope to a surface-acting antibiotic to both exert a direct effect and an immune-driven effect.
Microbiome modification:
CARB-X supported Vedanta Biosciences (CARB-X graduate) created VE707 to treat CRE, ESBL, and VRE infections, restoring healthy microbiota and halting the dissemination of MDR organisms.
Moving forward
Although the non-traditional approaches to fight anti-microbial resistance is being looked at favourably, the speed of development and market entry needs to be accelerated.
It is stipulated that just one non-traditional product would make it to the market in the next 10 years!
A strong policy framework and a concerted advocacy strategy running in parallel can provide the much-needed impetus to achieve acceleration and acceptance of these products. Low investments in the domain due to unclear regulatory parameters for demonstrating safety and efficacy of these products need resolution and clarity at the policy level.
Funding to drive sustainable investments in this space has been initiated by WHO and Drugs for Neglected Diseases initiative (DNDi) through their Global Antibiotic R&D Partnership (GARDP).
Many agencies have started aligning their efforts to promote innovative treatments against AMR, and are working closely with funding partners such as the CARB-X.
Similarly, the AMR Action Fund, a coalition of pharmaceutical companies, philanthropies, and the European Investment Bank, aims to strengthen and accelerate the most innovative and promising products in therapeutics against AMR for advance development and commercialization. However, on the other end of the spectrum it will be important to identify and promote consistent market demand for these products by the medical bodies, institutional buyers, retail customers and public health programmes so that it is lucrative for the pharmaceutical industry. Policy level interventions can enable this thrust by incentivizing the market players to invest resources and fast track products to the market.
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.
