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About 10-years ago, one of the major funders in this space asked me this question and I replied that I would give to Chemistry at the University of Oxford to find out if the clinical utility of beta-lactam antibiotics could be extended and to start to search for alternative clinically useful penicillin binding protein inhibitors.

My reason was that beta lactams have been the most successful antibiotic class and that we are likely to need them or a similar replacement in 30, 100 or 300-years.

Much to my surprise, last year, Ineos had the insight to do just this - £100m to create the Ineos Oxford Institute, which will focus on antimicrobial resistance. Although they have probably spread their remit a little widely, covering animal and human therapeutics, international surveillance, education and policy, this is without doubt an outstanding investment.

We just need more of the same, at every major University worldwide, not just by super-rich corporations, but also through charities and taxes to create the critical mass of excellence, eventually experience and ultimately output and impact that we need to address antimicrobial resistance for the long term.

The next post will look at what collaborative research can achieve with this type of funding.

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There are about 90 beta-lactam antibiotics with the characteristic amide-substituent on the lactam ring including examples from the penicillin, cephalosporin, cephamycin and oxacephem classes e.g.

7 of these antibiotics have an α-substituted lactam ring; cefminox, temocillin, cefotetan, cefoxitin, flomoxef, latamoxef and cefbuperazone – all with methoxy (MeO) substitutions.


It looks like the MeO substitution provided some advantage against serine lactamases of the time and temocillin still has attractive properties now with efficacy against ESBLs - see Stewart et al., 2022.

It is just an observation, but does anyone know if other substituents were exhaustively tried? A formamido substituent was tested - see Best et al., 1990.

Formamido substitution

Is there something unique about MeO?

Has this site of substitution been exhausted?

Does anyone know what happens if you added the alcohol found in carbapenems and penems at this position? e.g.

The marketed penems and carbapenems all have mono-substituted α-positions. Anyone know whether this position has been exhaustively explored e.g.?

It looks like future lactam-antibiotics may need to be partnered with serine and metallo-lactamase inhibitors. Building in some intrinsic resistance to serine lactamases may be beneficial and lead to BL/MBLI combinations that don’t need serine lactamase inhibitors to complicate the cocktail.

Interested in peoples reflections on past lactam programmes, thoughts about future ones, encouraging discussion......

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  • lloydczaplewski

In the 1980’s there must have been >1,000 scientists, including chemists, microbiologists, pharmacologists etc, working in the field of Β-lactam R&D in major Pharma like Beecham, Bristol Myers Sqibb, Dainippon Sumitomo Pharma, Eli Lilly, Merck, Pfizer and Roche. I’m sure this is not a complete list, but the point is that there were many teams of >100 people working on antibiotic R&D in most large Pharma companies. They delivered generations of antibiotics including penicillins, cephalosporins, carbapenems and monobactams.

Antibiotic resistance was a concern with each generation of compounds overcoming serine lactamase resistance of the time. Scientists were also tasked with altering the spectrum of the antibiotics to capture the infections of their time and to improve the pharmacology to create products that could be dosed less frequently to create a marketing advantage.

It became difficult to create a breakthrough differentiated product in this landscape, especially Β-lactam’s that could be dosed once or twice a day, and so return on investment into these large teams fell. Mergers created unsustainably large antibiotic capabilities and led to redundancies.

By the 1990’s critical mass of Β-lactam R&D had collapsed.

Many of the breakthroughs in recent years may have their foundations in the people and expertise from the 1980’s including ceftobiprole, avibactam and cefiderocol.

A key question we should all ask is whether Β-lactam R&D is complete and finished or whether the new challenges of resistance and spectrum and much less concern around dosage regimens lead to new opportunities for continued Β-lactam discovery and development.

I would really like to encourage a discussion, including those with the deep experience from the 70s, 80s and 90s, with the new generation of researchers, around what might be worth investigating to ensure that no Β-lactam “stone” is left unturned in the search for new generations of antibiotics – they may not be hugely innovative, but they might be useful!

What new chemistry is available to be deployed? What avenues merit further investigation?

At the very least, we could create a foundation of knowledge for future generations to make sure that the Β-lactam class is truly exhausted before we give up on it!

Over the coming months I will be adding to this blog with points for discussion. Hopefully some will enjoy the musing and perhaps even join in!

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