Antibiotic-Resistance-Breakers-ARBs

1. Antibiotic Resistance Breakers (ARBs) ARBs offer a means to both suppress the emergence of resistance and rescue the activity of existing drugs, offering an Orthogonal strategy complimentary to new antibiotic discovery

2. An Orthogonal Approach To Antibiotic Discovery Types of ARBs ARBs, sometimes referred as antibiotic adjuvants, are non-antibiotic moieties which do not have any antimicrobial activity on its own, but, in combination with antibiotics enhance their antimicrobial activity and help overcome resistance barriers. They can broadly be classified into 2 classes - Class 1 ARBs that help reduce the MIC of existing antibiotics (when used in combination), and Class 2 ARBs that act on hosts' defence mechanisms. Although the term Antibiotic Resistance Breakers is relatively new, the concept itself dates back to the early 1970s when the first beta-lactamase inhibitors (BLIs) were developed. Most BLIs can be thought of as ARBs that do not have any significant antimicrobial activity when used alone, but in combination with a beta-lactam antibiotic, help restore the activity against beta-lactamase producing organisms.

3. Key Antibiotics Requiring ARB Support Cell Wall Synthesis Disruptors Cell Membrane Synthesis Disruptors DNA Synthesis Disruptors Cephalosporins and carbapenems are critical antibiotics that need ARB support to maintain their effectiveness against resistant bacteria. Polymyxins are important antibiotics that require ARB protection to ensure continued efficacy against resistant strains. Fluoroquinolones need ARB support to overcome resistance mechanisms that have developed against this important class. 30S Ribosomal Subunit Inhibitors 50S Ribosomal Subunit Inhibitors Tetracyclines and aminoglycosides disrupt protein synthesis and require ARB protection to maintain their effectiveness. Macrolides are critical antibiotics that disrupt protein synthesis and need ARB support against resistant bacteria. ARBs that help in restoring activity against K. pneumoniae, E. coli, P. aeruginosa and A. baumannii, the four Gram- negative organisms whose resistance to antibiotics is of greatest concern (all of which produce carbapenemases and are thus resistant to many ³-lactam antibiotics), are of utmost importance.

4. Venus Remedies' ARB Product Pipeline VRL work on ARB Venus Remedies Limited has developed innovative ARB-based products to combat antimicrobial resistance. Their pipeline includes: CSE-1034 An advanced ARB formulation designed to overcome resistance mechanisms in critical bacterial infections VRP-001 A novel ARB combination targeting resistant Gram- negative pathogens These products specifically target the most concerning Gram- negative organisms: K. pneumoniae, E. coli, P. aeruginosa and A. baumannii, which produce carbapenemases and are resistant to many ³-lactam antibiotics. Venus Remedies is at the forefront of developing ARB solutions to combat the growing threat of antimicrobial resistance.

5. Reasons to Support ARB Development Target MDR Gram- negatives Address urgent multi1drug resistant threats Rising Resistance Antibiotic resistance is rapidly increasing Cost Savings Combine ARBs with existing drugs to save costs Faster Sequential Combinations Extend antibiotic lifespan via sequencing Development Cheaper, quicker path with higher success Repurposing drugs using ARBs overcomes many of the commercial barriers to developing new antibiotics and it is estimated that use of ARBs could salvage many of the 200 or so existing antibiotics for the future generations.

6. Traditional vs ARB Approach Comparing Approaches to Combat Antimicrobial Resistance Traditional Approach Focuses on developing entirely new antibiotic classes Requires extensive research and development Faces significant scientific and regulatory hurdles Typically takes 10+ years to bring to market ARB Approach Extends the life of existing antibiotics Reduces development time and costs Builds on known pharmacological profiles Provides immediate solutions to resistance problems The ARB approach represents a practical and efficient strategy to address the urgent global challenge of antimicrobial resistance while new antibiotic classes are being developed.

7. The Science Behind ARBs Design ARB Molecule Researchers design molecules that can specifically target and inhibit these resistance mechanisms Identify Resistance Mechanism Scientists identify specific bacterial resistance mechanisms that render antibiotics ineffective Combine with Antibiotic The ARB is combined with an existing antibiotic to create a formulation that overcomes resistance Clinical Implementation After clinical trials and regulatory approval, the ARB-antibiotic combination enters medical Test Effectiveness The combination is tested against resistant bacteria to confirm restored antibiotic activity practice

8. Target Pathogens for ARB Development K. pneumoniae P. aeruginosa A. baumannii E. coli Other pathogens ARBs that help in restoring activity against K. pneumoniae, E. coli, P. aeruginosa and A. baumannii, the four Gram- negative organisms whose resistance to antibiotics is of greatest concern (all of which produce carbapenemases and are thus resistant to many ³-lactam antibiotics), are of utmost importance. These pathogens represent the most urgent threats in the global antimicrobial resistance crisis and are the primary targets for ARB development efforts.

9. Economic and Practical Benefits of ARBs 200+ 50% 3-5x 10+ Antibiotics Potentially Salvaged Development Cost Reduction Higher Success Probability Years Saved ARBs provide immediate solutions while new antibiotic classes may take a decade or more to reach the market ARBs could potentially rescue more than 200 existing antibiotics, extending their useful lifespan for future generations ARB development can reduce costs by building on existing antibiotics with known pharmacological profiles ARB development has a significantly higher probability of success compared to developing entirely new antibiotic classes Repurposing drugs using ARBs overcomes many of the commercial barriers to developing new antibiotics and it is estimated that use of ARBs could salvage many of the 200 or so existing antibiotics for the future generations. This approach represents a practical and economically viable strategy to address the urgent global challenge of antimicrobial resistance.

10. The Future of ARB Technology 1 Current ARBs Today's ARBs like those in Venus Remedies' pipeline (CSE- 1034 and VRP-001) focus on restoring activity of existing antibiotics against resistant bacteria 2 Next Generation Future ARBs will target multiple resistance mechanisms simultaneously and may incorporate nanotechnology for improved delivery 3 Personalized ARBs Development of patient-specific ARB combinations based on the resistance profile of the infecting pathogen 4 Preventive Applications ARBs that can be used prophylactically to prevent the emergence of resistance in high-risk settings "If resistance develops to the first ARB combination, a second ARB could potentially rescue the same antibiotic. This cycle could be repeated many times, enabling old antibiotics to be used far into the future."