A class of dual activity antibiotics

The DASMA (Dual-Acting Small Molecule Antibiotics) program develops a new class of 2-in-1 molecules whose structure results from the combination of two active antibiotic moieties. The first, a fluoroquinolone moiety, inhibits bacterial type II topoisomerases (DNA-gyrase and topoisomerase IV) and therefore interferes with DNA replication, while the second, an oxazolidinone moiety, inhibits bacterial translation. Due to their dual mode of action, hybrid quinolonyl-oxazolidinone compounds can have an activity on a wide panel of pathogenic bacteria, including both wild-type and resistant strains.

While a first compound has provided solid proof-of-concept for these hybrid antibiotics – DNV3837, currently in phase II clinical trials –, several other candidates of the family have been isolated and display promising activity profiles, particularly on gram-negative bacteria.

A family of diverse compounds

The fluoroquinolone and oxazolidinone moieties of these dual compounds are covalently linked via a spacer. While the spacer in itself has no activity, it must be stable and plays an important role in modulating the activity and mode of action of the two active antibiotic moieties. Different members of the family with different activity profiles are therefore obtained by modifying the linker between the active elements.


Representation of the fluoroquinolone and oxazolidinone moieties covalently linked via a spacer

These dual activity antibiotics present a particular interest to treat infections with highly pathogenic gram-negative bacteria that have developed resistance to carbapenems, a class of antibiotics with a distinct mode of action, which act by inhibiting the synthesis of the bacterial cell wall (for example against carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa or Enterobacteriaceae). In addition and in spite of the shared mechanism of action, activity data suggests that some members of this class are also active against some fluoroquinolone-resistant bacteria, including fluoroquinolone-resistant Salmonellae, Neisseria gonorrhoeae and Shigella.

To date, 14 dual compounds have been identified as being active against a panel of reference gram-negative pathogens, among which 2 leads have been selected that display different activity profiles. Structure-activity relationships are currently under investigation to thoroughly characterize the compounds, before proceeding to lead optimization.