Table 2. Summary of Select Inhibitors or Activators of ClpC1, ClpP1P2, or Mtb20Sa.
| compound class | compound | synthetic (S) or natural product (NP) | target | method of identification | activity on R Mtb | activity on NR Mtb | activity in mouse model of TB | FOR | references |
|---|---|---|---|---|---|---|---|---|---|
| peptide, cyclic | cyclomarin A | NP | ClpC1 | WCS against M. bovis BCG | yes | yes | NT | <10–9 | (40, 235) |
| peptide, cyclic | ecumicin | NP | ClpC1 | WCS vs actinomycetes extracts against Mtb | yes | yes | yes | 1 × 10–8 | (38) |
| peptide, cyclic | rufomycin | NP | ClpC1 | WCS vs actinomycetes extracts against Mtb | yes | NT | NT | NT | (197) |
| peptide, lasso | lassomycin | NP | ClpC1 | WCS of NP extracts against Mtb | yes | yes | NT | NT | (39) |
| acyldepsipeptide | ADEP-2 | NP | ClpP1P2 | N/A: previously shown to be active against S. aureus(42) | yes | NT | NT | 1 × 10–6(for S. aureus) | (42, 98, 196) |
| peptidyl boronate | examples: N-(2-(3,5-difluorophenyl)acetyl-Trp-boroMet); N-(Picolinoyl)-Ala-Lys-boroMet | S | ClpP1P2 | blocked tripeptide-AMC library to determine substrate preferences followed by rational design of inhibitors | yes | NT | NT | NT | (207) |
| peptidyl boronate | bortezomib (Velcade), MLN-273 | S | Mtb20S and ClpP1P2 (bortezomib); Mtb20S (MLN-273) | bortezomib: target-based whole-cell screen against M. smegmatis strain carrying SsrA-tagged GFP; MLN273: N/A | yes | yes | NT | NT | (107, 119, 203) |
| β-lactones | β-lactone 7 | S | ClpP1P2 | whole-cell screen of racemic mixture (14 scaffolds) of β-lactones against M. smegmatis | yes | NT | NT | NT | (201) |
| N, C-capped dipeptide | DPLG-2 | S | Mtb20S | purified recombinant Mtb20S-OG, hydrolysis of AMC-linked substrate | no | yes | NT | NT | (211) |
| oxathiazol-2-one | GL-5 | S | Mtb20S | purified recombinant Mtb20S-OG, hydrolysis of AMC-linked substrate | no | yes | NT | NT | (41) |
| styryl-oxathiazol-2-one | compound 17 | S | Mtb20S | purified recombinant Mtb20S-OG, hydrolysis of AMC-linked substrate | no | yes | NT | NT | (210) |
| macrolactam | syringolin analogues-compound 13 | S based on NP | Mtb20S | purified recombinant Mtb20S-OG, hydrolysis of AMC-linked substrate | NT | yes | NT | NT | (213) |
| epoxyketone peptide | epoxomicin | NP | Mtb20S | NA | NT | yes | NT | NT | (119) |
| lipopeptide aldehyde | fellutamide B | NP | Mtb20S | purified recombinant Mtb20S-OG, hydrolysis of AMC-linked substrate | NT | NT | NT | NT | (209, 236) |
| NA | MTBA, MTBB | S | Pup/Mpa interaction | in-cell STINT-NMR | NT | yes | NT | NT | (212) |
a
Abbreviations: NA = not applicable; NT = not tested or not found in the literature; S = synthetic; NP = natural product; FOR = frequency of resistance; Mtb20S = 20S proteasome (PrcBA); OG = open gate; AMC = aminomethyl coumarin; GFP = green fluorescent protein; R = replicating; NR = nonreplicating.