α-substituted beta-lactam antibiotics: Is there anything left to explore?

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.

Temocillin

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......