Antibacterial Drug Development: A New Approach Is Needed for the Field to Survive and Thrive

Abstract

It is often said that the marketplace for new antibiotics is broken. This notion is supported by the observation that many recently-approved antibiotics to treat drug-resistant bacteria have failed commercially in a spectacular fashion. Today, companies with peak market-cap values in excess of USD 500 million to 1 billion prior to product launch regularly sell for pennies on the dollar a few years after market introduction. It is possible, however, that the market is not as broken as we perceive. That is, in the collective mind of the clinician, recently-approved antibiotics may be too-poorly differentiated to justify their broad use and inordinate cost relative to those already existing. Perhaps we in the antibacterial drug development field must change our way of thinking if we are to survive and thrive. Rather than reflexively developing new β-lactam-β-lactamase inhibitor combinations for every new enzyme that evades our current inhibitors, we should focus discovery and development efforts on agents that revolutionize how we potentiate antibiotics. To this end, there has been renewed interest in phage therapies, virulence inhibitors, bacterial growth rate modulators, monoclonal antibodies, and other approaches to augment antibiotic effects. Herein, we suggest that the unmet medical need is less about adding poorly-differentiated antibiotics to our armamentarium and more about the need for innovation in how we augment antibiotic regimen effects.

Understanding eco-immunology of bacterial zoonoses and alternative therapeutics toward "One Health"

“…At the end of the lytic lifecycle, dsDNA phage encodes holin and endolysin proteins to lyse the bacterial cell wall and additional spanning protein in the case of Gram-negative bacteria to break the outer membrane. Exebacase (also called as CF-301) and N-Rephasin SAL200 (tonabacase) are the lysins used for the treatment of bacterial infections [63,64]. In addition, it has been found that bacteria show no resistance to endolysins due to their mechanism of action and their structure [65].…”

Benefits of Combined Phage–Antibiotic Therapy for the Control of Antibiotic-Resistant Bacteria: A Literature Review

“…Yet, in the last two decades, the market for antibiotics has been broken due to the high cost of developing new molecules. As the hope of repeating the therapeutic breakthroughs of the 20th century is rapidly fading away, there is an urgent need to develop novel approaches for the control of antibiotic-resistant bacteria [ 2 ].…”

The importance of pharmacokinetics and pharmacodynamics in antimicrobial drug development and their influence on the success of agents developed to combat resistant gram negative pathogens: A review

“…Since 2014, only nine antibiotics have been approved that target resistant Gram-negative pathogens ( Table 1 ) and 78% of major pharmaceutical companies have scaled back or cut antibiotic research due to developmental challenges ( PEW, 2021 ). Many of these challenges include monetary costs, time, feasibility of clinical trials, regulatory barriers, and low return on investment ( Luepke and Mohr, 2017 ; Bhavnani et al, 2020 ; Safir et al, 2020 ). As resistance has increased and drug development slowed, pharmacokinetic (PK) and pharmacodynamic (PD) studies have become even more important as a means of optimizing and preserving the agents currently available.…”