Qpex employee working in the lab.

Science

Our science platform includes approaches to restore anti-infective potency against drug-resistant bacteria, complementing Shionogi’s longstanding global efforts to develop critically needed antimicrobials. Our strategy is to improve existing drug classes, identify underexploited targets and subsequent treatments, and discover non-antibiotic therapies designed to neutralize resistance mechanisms. Our science addresses not only class-based resistance but also intrinsic mechanisms that are frequently responsible for multidrug resistance related to efflux and permeability mutations.

Discovery

Some of the most productive approaches over the last 50 years were made in classes of drugs based on the penicillin molecule—these drugs are often considered first-line treatments worldwide.1,2 One of our approaches is to help improve existing, clinically proven anti-infectives by combining them with nonantibiotic drugs that can inhibit resistance mechanisms. We continue to build on these improvements by leveraging our decades of learnings about the pharmacology and microbiological properties of these drug classes in patient populations.

With our research strategies, we aim to restore anti-infective potency against drug-resistant bacteria through a balanced approach, with a focus on clinical usefulness, to direct discovery efforts. 

The challenge lies in discovering new chemical classes of drugs with novel mechanisms of action that are safe for use in humans, but it can be done. For example, our scientists discovered, developed and obtained regulatory approvals for a first-in-class boronate beta-lactamase inhibitor. 

 

Beta-lactam Anti-Infectives: The Usefulness of This Critical Class of Anti-Infectives Is Being Lost

The discovery of penicillin by Alexander Fleming in the 1920s was one of the most consequential advances in medicine in the last century. Penicillin and the subsequent improvements in newer forms of penicillin-like drugs such as cephalosporins and carbapenems have positioned these drugs as preferred choices for the treatment of infections in many settings.3,4,5

Alarmingly, resistance in Gram-negative bacteria to the beta-lactam anti-infective class is reversing the gains made over the last 35 years with these new drugs. The loss of this class of drugs became a tipping point in the lack of effective anti-infectives for the treatment of serious infections.6

The most common form of resistance to the penicillin, cephalosporin and carbapenem classes of drugs occurs due to the production of a bacterial enzyme that destroys the anti-infective. These enzymes, called beta-lactamases, have spread among bacteria worldwide.7,8

Beta-lactamase inhibitors are drugs that neutralize the bacterial enzymes responsible for treatment resistance to beta-lactam antibiotics, the most important class of drugs used to treat serious infections in hospitals worldwide. Beta-lactamase inhibitors are administered in combination with beta-lactam antibiotics and improve their antimicrobial activity.9

Enzyme Inhibition to Overcome Resistance

Discovery of a New Drug Class Restores Proven Anti-Infectives

The beta-lactam class of drugs, which includes penicillin, is among the most important and widely used antimicrobials worldwide. Combinations of beta-lactam antibiotics and beta-lactamase inhibitors have become an important strategy to overcome emerging resistance to new drugs.10

Scientists at Qpex previously discovered a new chemical class of drugs that specifically inhibits beta-lactamase enzymes, which destroy penicillin-like drugs. Inhibiting these enzymes can overcome the resistance to penicillin-like drugs in many Gram-negative bacteria.11 This new chemical class of drugs made use of the element boron, an atom that had not previously been widely used in drugs because of the need for special knowledge of how to create new boron-containing molecules. This discovery resulted in the first member of a new class of boron-containing drugs targeting bacterial beta-lactamases, which demonstrated unique binding and pharmacological properties.11 It was tested in patients and, ultimately, approved by the U.S. Food and Drug Administration (FDA) as well as regulators in Europe, such as the European Medicines Agency (EMA).

“One sometimes finds what one is not looking for. When I woke up just after dawn on September 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I suppose that was exactly what I did.”

Alexander Fleming

 

Innovation Leads to Improvements in Our New Drug Class

Qpex scientists have improved the properties of this new class of beta-lactamase inhibitors through the discovery of xeruborbactam, an investigational drug formerly known as QPX7728.12 These improvements include expanding the spectrum of inhibition of clinically important serine and metallo-beta-lactamases in Enterobacterales, Acinetobacter spp. and Pseudomonas aeruginosa, as well as reducing the effects of multidrug resistance mechanisms (related to efflux and permeability). High-resolution structures have shown xeruborbactam co-crystalized with multiple beta-lactamases. Nonclinical studies have shown that xeruborbactam inhibits multiple beta-lactamases, preventing these enzymes from breaking down cefiderocol and restoring activity in vitro.13 In vitro studies show that xeruborbactam inhibits many bacterial beta-lactamases associated with resistance to beta-lactam antibiotics.14,15

Qpex’s boronate inhibitors of beta-lactamase have the potential to restore the effectiveness of beta-lactam antibiotics against pathogens that cause serious infections in both hospital and non-hospital settings.

Xeruborbactam is advancing in clinical trials in the IV form with cefiderocol (S-649228) and in a prodrug form with ceftibuten (S-743229), an oral antibiotic discovered by Shionogi.16

References

  1. Murugaiyan J, et al. Progress in Alternative Strategies to Combat Antimicrobial Resistance: Focus on Antibiotics. Antibiotics (Basel). 2022 Feb 4;11(2):200. doi:10.3390/antibiotics11020200. ↩︎
  2. Aminov RI. A brief history of the antibiotic era: lessons learned and challenges for the future. Front Microbiol. 2010 Dec 8;1:134. doi:10.3389/fmicb.2010.00134. ↩︎
  3. Penicillin. National Library of Medicine. Accessed December 6, 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK554560/#:~:text=Indications-,Penicillin%20is%20one%20of%20the%20most%20commonly%20used%20broad%2Dspectrum,lactam%20antibiotic%20class%20of%20drugs.&text=Penicillin%20G:,Anthrax%20caused%20by%20Bacillus%20anthracis. ↩︎
  4. Kuriyama T, Karasawa T, Williams DW. Chapter Thirteen – Antimicrobial Chemotherapy: Significance to Healthcare. ScienceDirect, 2014;209–244.
    doi:10.1016/B978-0-12-397043-5.00013. ↩︎
  5. Cephalosporins. National Library of Medicine. Accessed December 6, 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK551517/. ↩︎
  6. Garcia-Bustos V, et al. Resistance to beta-lactams in Gram-negative bacilli: relevance and potential therapeutic alternatives. Rev Esp Quimioter. 2022 Sep;35 Suppl 2(Suppl 2):1-15. doi:10.37201/req/s02.01.2022. Epub 2022 Oct 4. ↩︎
  7. Li X-Z, Mehrotra M, Ghimire S, Adewoye L. beta-Lactam resistance and beta-lactamases in bacteria of animal origin. Veterinary Microbiology, 2007 Apr;121(3-4), 197–214. doi:10.1016/j.vetmic.2007.01.015. ↩︎
  8. Reygaert WC. An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol. 2018 Jun 26;4(3):482-501. doi:10.3934/microbiol.2018.3.482. ↩︎
  9. Beta-Lactamase Inhibitors. National Library of Medicine. Accessed December 6, 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK557592/. ↩︎
  10. Abodakpi H, et al. What the Clinical Microbiologist Should Know About Pharmacokinetics/Pharmacodynamics in the Era of Emerging Multidrug Resistance: Focusing on β-Lactam/β-Lactamase Inhibitor Combinations. Clin Lab Med. 2019 Sep;39(3):473-485. doi:10.1016/j.cll.2019.05.006. ↩︎
  11. Hecker SJ, et al. Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases. J Med Chem. 2015 May 14;58(9):3682-92. doi:10.1021/acs.jmedchem.5b00127. ↩︎
  12. Hecker SJ, et al. Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases. J Med Chem. 2020 Jul 23;63(14):7491-7507. doi:10.1021/acs.jmedchem.9b01976. ↩︎
  13. Yamano Y, Hara T, Ishibashi N, Miyagawa D, Onishi M, et al. The impact of xeruborbactam on in vitro activity of cefiderocol against a challenge panel of Acinetobacter baumannii enriched in isolates with increased cefiderocol MICs. Presentation 514. Presented at IDWeek 2-24, Los Angeles, CA: October 16-19, 2024. ↩︎
  14. Tsivkovski R, Totrov M, Lomovskaya O. Biochemical Characterization of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases. Antimicrobial Agents and Chemotherapy. 2020 May 21;64(6):e00130-20.doi:10.1128/AAC.00130-20. ↩︎
  15. Lomovskaya O, et al. In vitro potency of xeruborbactam in combination with multiple β-lactam antibiotics in comparison with other β-lactam/β-lactamase inhibitor (BLI) combinations against carbapenem-resistant and extended-spectrum β-lactamase-producing Enterobacterales. Antimicrob Agents Chemother. 2023 Nov 15;67(11):e0044023. doi:10.1128/aac.00440-23. ↩︎
  16. Long-term commitment to improving R&D to provide novel treatments for infectious diseases. Shionogi & Co., Ltd. Accessed February 13, 2025. Available at: https://www.shionogi.com/global/en/sustainability/amr/commitment.html. ↩︎
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