Antibiotics in the clinical pipeline in October 2019

Abstract

The development of new and effective antibacterial drugs to treat multi-drug resistant (MDR) bacteria, especially Gram-negative (G-ve) pathogens, is acknowledged as one of the world's most pressing health issues; however, the discovery and development of new, nontoxic antibacterials is not a straightforward scientific task, which is compounded by a challenging economic model. This review lists the antibacterials, β-lactamase/β-lactam inhibitor (BLI) combinations, and monoclonal antibodies (mAbs) first launched around the world since 2009 and details the seven new antibiotics and two new β-lactam/BLI combinations launched since 2016. The development status, mode of action, spectra of activity, lead source, and administration route for the 44 small molecule antibacterials, eight β-lactamase/BLI combinations, and one antibody drug conjugate (ADC) being evaluated in worldwide clinical trials at the end of October 2019 are described. Compounds discontinued from clinical development since 2016 and new antibacterial pharmacophores are also reviewed. There has been an increase in the number of early stage clinical candidates, which has been fueled by antibiotic-focused funding agencies; however, there is still a significant gap in the pipeline for the development of new antibacterials with activity against β-metallolactamases, orally administered with broad spectrum G-ve activity, and new treatments for MDR Acinetobacter and gonorrhea.

Fig. 1

New antibacterial and BLI classes January 2000 to October 2019 with new classes highlighted

Fig. 2

Structures of the recently launched antibacterial drugs

Fig. 3

Structures of the recently β-lactam/β-lactamase inhibitor (BLI) combinations

Fig. 4

Structures of antibacterials in the NDA and MAA development stage

Fig. 5

Structures of compounds in phase-III clinical trials

Fig. 6

Structures of NP-derived compounds in phase-II clinical trials

Fig. 7

Structures of synthetic compounds in phase-II clinical trials

Fig. 8

Structures of NP-derived compounds in phase-I clinical trials

Fig. 9

Structures of synthetic-derived compounds in phase-I clinical trials

Fig. 10

Structure of the mAb-rifamycin antibiotic conjugate in phase-I trials

Fig. 11

Structures of BLIs and associated β-lactam antibiotics in phase-III clinical trials and clavulanic acid (67)

Fig. 12

Structures of BLIs and associated β-lactam antibiotics in phase-I clinical trials

Fig. 13

Compounds under clinical evaluation divided into development phases and their lead derivation source: natural product (NP), synthetic (S), protein/mammalian peptide (P), β-lactam/β-lactamase inhibitor (BLI) combinations, and antibody drug conjugate (ADC)

Fig. 14

Comparison of the numbers of compounds undergoing clinical development as of 2011 [3], 2013 [2], 2015 [1], and 2019 by development phase

Fig. 15

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

Fig. 16

Comparison of the numbers of novel antibacterial pharmacophores undergoing clinical development in 2011 [3], 2013 [2], 2015 [1], and 2019 by development phase