Delamanid or pretomanid? A Solomonic judgement!

Abstract

Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.

Activity of Drug Combinations against Mycobacterium abscessus Grown in Aerobic and Hypoxic Conditions

“…Previous studies by our group and other investigators reported consistent activities of nitrocompounds [19,20], including metronidazole (MTR), pretomanid (PRT, formerly PA-824) and nitazoxanide (NTZ), alone and in combination, against AR and NR Mtb [21][22][23][24][25][26]. Recent trials demonstrated the potential of PRT-containing regimens against drug-susceptible and -resistant pulmonary tuberculosis (TB) [27,28].…”

Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets

“…However, this regimen should only be administered under operational research conditions and when BDQ and linezolid have not been previously used [ 30 ]. PMD, which is a nitroimidazole derivative similar to DLM, was the third and most recently approved drug to be added to the TB treatment arsenal [ 36 ]. The US FDA granted its approval for PMD in 2019 as a part of the BPaL regimen and limited its indication to adults with XDR-TB or non-responsive or drug-intolerant MDR-TB [ 36 ].…”

Synthesis and Characterization of Phenylalanine Amides Active against Mycobacterium abscessus and Other Mycobacteria

“…Under normoxic conditions, pretomanid is converted into reactive intermediates that interfere with mycolic acid synthesis, while in anaerobic environments, it acts as an NO donor that effectively poisons the respiration of mycobacteria. 15,16 By combining bedaquiline, pretomanid, and linezolid, a new therapeutic regimen for treatment of MDR tuberculosis has been established. 17 NTM have come into scientific focus in recent years, owing to the fast-growing, multidrug-resistant Mabs and the Mycobacterium avium complex (MAC), which have emerged as problematic opportunistic pathogens.…”

“…Research efforts have led to the approval of two new drugs: bedaquiline and pretomanid. − Bedaquiline acts by inhibiting mycobacterial ATP synthase, while pretomanid has a rather complex mechanism of action. Under normoxic conditions, pretomanid is converted into reactive intermediates that interfere with mycolic acid synthesis, while in anaerobic environments, it acts as an NO donor that effectively poisons the respiration of mycobacteria. , By combining bedaquiline, pretomanid, and linezolid, a new therapeutic regimen for treatment of MDR tuberculosis has been established …”