Antibiotics in the clinical pipeline as of December 2022

Abstract

The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed.

Fig. 1

New small molecule antibacterial drugs and BL/BLI combinations launched from January 2000 to December 2022 with new classes highlighted

Fig. 2

Structures of the recently lauched antibacterial drugs

Fig. 3

Structure of the antibacterial in the NDA and MAA development stage (Table 3)

Fig. 4

Structures of compounds in phase-III clinical trials (Table 3)

Fig. 5

Structures of NP-derived compounds in phase-II clinical trials (Table 4)

Fig. 6

Structures of synthetic compounds in phase-II clinical trials (Table 4)

Fig. 7

Structures of small molecule non-traditional antibacterials in phase-II clinical trials (Table 4)

Fig. 8

Structures of NP and peptide-derived compounds in phase-I clinical trials (Table 5)

Fig. 9

Structures of synthetic-derived compounds in phase-I clinical trials (Table 5)

Fig. 10

Structures of publicly disclosed small molecule non-traditional antibacterials in phase-I clinical trials (Table 5)

Fig. 11

Structures of BLI and associated β-lactam antibacterial in NDA/MAA filing (Table 6)

Fig. 12

Structures of BLIs in phase-III clinical trials (Table 6)

Fig. 13

Structures of BLIs and associated β-lactam antibiotics in phase-I clinical trials (Table 6)

Fig. 14

Compounds under clinical evaluation divided into development phases and their lead derivation source: natural product (NP) (NP-derived and NP-BLI), protein/mammalian peptide (P-derived) and synthetic (S) (S-derived and S-BLI)

Fig. 15

Comparison of the numbers of compounds undergoing clinical development as of 2011 [26], 2013 [25], 2015 [24], 2019 [23] and 2022 by development phase

Fig. 16

Antibacterial compounds [natural product (NP), synthetic (S), protein/mammalian peptide (P)] and β-lactamase inhibitors (BLI)] with new antibacterial pharmacophores divided into development phases and their lead derivation source

Fig. 17

Comparison of the numbers of novel antibacterial pharmacophores undergoing clinical development in 2011 [26], 2013 [25], 2015 [24], 2019 [23] and 2022 by development phase