Scientists have discovered a new potential treatment that could reverse antibiotic resistance in different Gram-negative bacteria that cause conditions including urinary tract infections, sepsis, or pneumonia. The collaborative research, headed by a team at the Ineos Oxford Institute (IOI) for Antimicrobial Research at the University of Oxford, and several institutions across Europe, found that a new class of enzyme blockers, called indole carboxylates (InCs), inhibits the activity of metallo-β-lactamase (MBL) resistance enzymes produced by bacteria. These MBL enzymes break down last-resort carbapenem antibiotics, making the organisms resistant to therapy. The team’s studies showed that using indole carboxylates to block MBL enzymes allowed β-lactam antibiotics to attack and kill bacteria such as E. coli in the lab, and in murine infections in vivo.
Study lead Christopher Schofield, PhD, academic lead (chemistry), Ineos Oxford Institute, said, “The collaborative efforts of academics and industry scientists have discovered a brand new class of drug that can shut down one of the ways bacteria fight back against antibiotics.” The researchers are continuing their work with the indole carboxylates, with a view to future clinical trials.
Schofield and colleagues reported on their studies in Nature Chemistry, in a paper titled, “Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors,” in which they concluded, “These results reveal that InCs have a substantial potential for clinical development with β-lactam antibiotics. We are actively progressing InCs towards clinical trials in humans, with a particular focus on low-to-middle income countries in which NDM-mediated resistance is widespread.”
The increase in antibiotic resistance raises concerns that, at least in some regions of the world, the situation is returning to a pre-antibiotic era, in particular for Gram-negative infections, the authors stated. The World Health Organization (WHO) estimates that by 2050, 10 million deaths annually might be due to antimicrobial resistance, and the number of antibiotic resistance-related deaths will overtake the number of cancer-related deaths, making antibiotic resistance one of the most pressing health problems faced by humanity today. “An increase in antimicrobial resistance is absolutely inevitable,” Schofield stated. “It is a massive problem because collectively we haven’t been making enough new clinically useful antibiotics. As a society, we must find ways both to make new antibiotics and protect the ones we have. The alternative is that routine modern medicine will be disrupted in a manner simply too horrendous to conceive.”
Carbapenems such as meropenem, are a group of vital, often “last-resort” antibiotics that are used to treat serious multi-drug resistant (MDR) infections when other antibiotics, such as penicillin, have failed. However, some bacteria have found a way to survive carbapenem therapy by producing metallo-β-lactamases that break down the carbapenem antibiotics, stopping them from working. And given that there are few novel anti-Gram-negative drugs entering clinical trials, the authors noted, “… overcoming resistance to restore the activity of existing drugs with excellent safety records, for example, β-lactams, is important … The development of MBL inhibitor(s), in particular to protect carbapenems, is thus an unmet clinical need, especially in the developing world, where MBL-producing bacteria are widely disseminated.”
Carbapenems work in a similar way to penicillin and other related antibiotics called β-lactams—they stop bacteria from forming new cell walls when they try to grow and multiply, which kills the bacteria. Carbapenems are more stable than other similar antibiotics, and many of the methods bacteria employ to resist antibiotics don’t work on carbapenems. However, resistance to carbapenems has arisen, through, for example, genes that code for MBLs, which can quickly pass from bacteria to bacteria. There is no licensed drug that targets MBLs, and only one in clinical trials.
For their newly reported study, funded by the Innovative Medicines Initiative (IMI) through the European Lead Factory (ELF) and the European Gram-Negative Antibacterial Engine (ENABLE) programs, the researchers first screened hundreds of thousands of chemicals to see which would attach tightly to MBLs to stop them working, and which didn’t react with any human proteins.
The study identified indole carboxylates as promising new candidates, and using crystallographic evaluation to take a closer look at how they work, the researchers showed that the new InC molecules attach to MBLs in a completely different way to any other drug, in that they imitate the interaction of the antibiotic with the MBLs. This clever Trojan Horse trick allows the potential drugs to be highly effective against a very wide range of MBL-producing superbugs. “ … structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance,” they wrote. The InCs have an unprecedented MBL binding mode, which is different with regards to those of both carbapenem substrates and their hydrolysis products.”
The researchers then chemically changed aspects of the compounds to make them as effective as possible. “The carbapenem-type binding mode of the InCs enabled us to fine-tune MBL activity,” they commented. The team tested their compounds, in combination with carbapenem antibiotics, against multi-drug resistant bacteria in vitro, and also in vivo, in mice. The studies showed that treatment using the new drug candidate compounds—and one in particular, designated InC 58—in combination with carbapenems was five times more potent against severe bacterial infections than treatment using carbapenems alone, and at a less concentrated dose.
Importantly, these potential drugs show only mild side effects in mice. “InCs protect carbapenems from MBL activity in MDR and extensively drug-resistant (XDR) Gram-negative pathogens, as shown by in vitro and in vivo mouse infection model,” the researchers noted. “InC 58 is tolerated well by mice and when combined with meropenem it shows substantial in vivo efficacy in multiple murine peritonitis/sepsis and thigh models with infection by carbapenem-resistant XDR strains.”
Schofield commented, “This research is the culmination of years of work, from screening huge libraries of chemicals, through to testing the best drug candidates in preclinical studies in the lab. We are actively progressing this new drug type towards clinical trials in people, most importantly in lower and middle income countries where resistance to carbapenem antibiotics is widespread.”
Tim Walsh, PhD, academic lead (biology), Ineos Oxford Institute at the University of Oxford, further noted, “Academia, given the space to create, can produce something amazing—and that’s what we have seen here. With the fantastic support we have received from INEOS, we can replicate this type of drug discovery program within the IOI for multiple different bacterial targets and applications.
“As well as drugs that overcome resistance to current antibiotics, in the IOI we wish to discover entirely new types of antibiotics—not only to fight bacteria that cause infections in humans, but in bacteria that affect farm animals. These animals, such as chickens and pigs, are a source of human antimicrobial resistance, so we’re looking to develop drugs to use exclusively in agriculture and help protect against multidrug-resistant infections.”
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