Table 1. Selected optimization... | Rockefeller University Press

Table 1.

Selected optimization opportunities for oral treatment of M. abscessus lung disease

Antibiotic class	Target	Strengths	Strategies to overcome weakness(es) of each class
Rifamycin	RNA polymerase	Target clinically validated; bactericidal; direct repurposing possible (rifabutin)	Optimize potency by blocking intrabacterial metabolism
Fluoro-quinolone	DNA gyrase	Target clinically validated; bactericidal	Optimize potency by overcoming intrinsic resistance
Oxazo-lidinone^{^a}	Ribosomal RNA	Target clinically validated; large compound collections available	Increase therapeutic window (potency/inhibition of mitochondrial protein synthesis)
β-lactam/β-lactamase inhibitor	L,D-and D,D-transpeptidases; carboxypeptidase; β-lactamases	Targets clinically validated; effective and approved oral β-lactamase inhibitors exists; bacteriolytic	Combine approved and orally bioavailable agents to overcome target redundancy
Oxaborole	Leucyl transfer RNA synthetase	Novel target, no pre-existing resistance	Clinical trials required
Diaryl-quinoline^{^b}	ATP synthase	Target clinically validated	Clinical trials required; develop analogs with faster bactericidal activity and lower hydrophobicity
Amino-glycoside	Ribosomal RNA	Target clinically validated; apramycin partially overcomes intrabacterial inactivation	Develop orally bioavailable analogs; improve therapeutic window
Tetracycline	Ribosomal RNA	Target clinically validated; omadacycline as a promising clinical trial candidate	Optimize potency; prevent intrabacterial metabolism

Antibiotic class	Target	Strengths	Strategies to overcome weakness(es) of each class
Rifamycin	RNA polymerase	Target clinically validated; bactericidal; direct repurposing possible (rifabutin)	Optimize potency by blocking intrabacterial metabolism
Fluoro-quinolone	DNA gyrase	Target clinically validated; bactericidal	Optimize potency by overcoming intrinsic resistance
Oxazo-lidinone^{^a}	Ribosomal RNA	Target clinically validated; large compound collections available	Increase therapeutic window (potency/inhibition of mitochondrial protein synthesis)
β-lactam/β-lactamase inhibitor	L,D-and D,D-transpeptidases; carboxypeptidase; β-lactamases	Targets clinically validated; effective and approved oral β-lactamase inhibitors exists; bacteriolytic	Combine approved and orally bioavailable agents to overcome target redundancy
Oxaborole	Leucyl transfer RNA synthetase	Novel target, no pre-existing resistance	Clinical trials required
Diaryl-quinoline^{^b}	ATP synthase	Target clinically validated	Clinical trials required; develop analogs with faster bactericidal activity and lower hydrophobicity
Amino-glycoside	Ribosomal RNA	Target clinically validated; apramycin partially overcomes intrabacterial inactivation	Develop orally bioavailable analogs; improve therapeutic window
Tetracycline	Ribosomal RNA	Target clinically validated; omadacycline as a promising clinical trial candidate	Optimize potency; prevent intrabacterial metabolism

Linezolid recommended for treatment of M. abscessus lung disease but with poor tolerability profile leading to frequent discontinuation.

Bedaquiline sporadically used off-label (Egorova et al., 2021).