Antibacterials with Novel Chemical Scaffolds in Clinical Development

Abstract

The rise of antimicrobial resistance represents a significant global health threat, driven by the diminishing efficacy of existing antibiotics, a lack of novel antibacterials entering the market, and an over- or misuse of existing antibiotics, which accelerates the evolution of resistant bacterial strains. This review focuses on innovative therapies by highlighting 19 novel antibacterials in clinical development as of June 2024. These selected compounds are characterized by new chemical scaffolds, novel molecular targets, and/or unique mechanisms of action, which render their potential to break antimicrobial resistance particularly high. A detailed analysis of the scientific foundations behind each of these compounds is provided, including their pharmacodynamic profiles, current development state, and potential for overcoming existing limitations in antibiotic therapy. By presenting this subset of chemically novel antibacterials, the review highlights the ability to innovate in antibiotic drug development to counteract bacterial resistance and improve treatment outcomes.

Fig. 1

Overlay of the crystal structures of moxifloxacin (green), zoliflodacin (yellow) and gepotidacin (pink) in a ternary complex with S. aureus DNA gyrase (GyrA: beige; GyrB: coral) and doubly nicked DNA (blue) with magnesium (purple) (PDB: 5CDQ, 8BP2, and 6QTK) [–34]

Fig. 2

Structure of gepotidacin

Fig. 3

Structure of zoliflodacin

Fig. 4

Structure of BWC0977

Fig. 5

Structure of DSTA4637S

Fig. 6

a Structure of zosurabalpin. b Schematic structure of the lipopolysaccharide (LPS) transporter. Adapted from [61]. c Cryo-EM structure of zosurabalpin (green) with Acinetobacter baylyi LptB₂FG (F: blue; G: red) and Acinetobacter LPS (grey) (PDB: 8FRN) [61]

Fig. 7

Structure of murepavadin

Fig. 8

a Structure of afabicin. The cleavage site to give the active agent afabicin dephospho is indicated by a dotted line. b Crystal structure of afabicin (green) with S. aureus FabI (beige) and the unnatural substrate 3´NADPH (pink) (PDB: 4FS4). Besides interactions with the target, the carbonyl of afabicin desphospho cis-amide can interact with NADPH [80]

Fig. 9

Bacterial fatty acid biosynthesis and the inhibition of the FabI-catalyzed step by afabicin desphospho. Adapted from [85]

Fig. 10

a Structure of TXA709. The cleavage site to give the active agent TXA707 is indicated by a dotted line. b TXA707’s mechanism of action. Adapted from [88]. c Crystal structure of TXA 707 binding to an inter-subdomain pocket of Staphylococcus aureus FtsZ (PDB: 5XDT) [89]

Fig. 11

a Structure of G0775. b Mechanism of action of optimized arylomycin with activity against Gram-negative bacteria. CP cytoplasm, IM inner membrane, OM outer membrane, PP periplasm. Adapted from [101]

Fig. 12

Structure of voxvoganan

Fig. 13

Structure of PL-18

Fig. 14

Amino acid sequence of PLG0206

Fig. 15

Structure of OMN6

Fig. 16

Structure of brilacidin

Fig. 17

a Penicillin hydrolysis by serine β-lactamases (top) and a di-zinc B1 metallo-β-lactamase (bottom). B_A base for acylation step, B_D base for the deacylation step. Adapted from [152, 167]. b Dual mechanism of action of some bicyclic boronate β-lactamase inhibitors based on the crystal structures of taniborbactam (PDB: 6SP6 and 6SP7) and xeruborbactam (PDB: 6V1J and 6V1P) [168, 169]

Fig. 18

Structure of taniborbactam

Fig. 19

Structure of xeruborbactam

Fig. 20

Structure of KSP-1007

Fig. 21

a Structure of fluorothiazinone. b Schematic structure of a bacterial type 3 secretion system injecting effector proteins from the bacterial cytoplasm into the host cell. IM inner membrane, OM outer membrane. Adapted from [193]

Fig. 22

a Structure of M4284. b Schematic structure of the type 1 pilus of uropathogenic E. coli, displaying FimH at the tip. Adapted from [217]. c Cellular mechanism of action of FimH antagonists. Adapted from [218]