Anti-tuberculosis drugs: targeting outer membrane channel proteins, ion channel blockers and the use of cucurbit[7]uril as an excipient to improve oral drug delivery and efficacy against resistant Mycobacterium Tuberculosis
| Autor: | Fong, Clifford |
|---|---|
| Přispěvatelé: | Eigenenergy, Eigenenergy Adelaide, South Australia, Australia |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CpnT protein ion channel
cucurbit[7]uril HOMO-LUMO energy gap isoniazid drug resistance pyrazinamide excitation energy quantum mechanics ion channel inhibitors ethambutol Mycobacterium tuberculosis [CHIM.THER]Chemical Sciences/Medicinal Chemistry outer membrane cell membrane lipophilicity macrophages [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry TD DFT binding energy inclusion complexes |
| Zdroj: | [Research Report] Eigenenergy Adelaide, South Australia, Australia. 2021 |
| Popis: | This study shows that the antibiotic resistance of 14 drugs is primarily dependent upon the lipophilicity ofthe drugs for wt M. bovis BCG and the mutants cpnT::Tn/mspA and cpnT::Tn/cpnT. The outer membranechannel protein CpnT of M. tuberculosis is essential for persistence and toxicity of the pathogen inmacrophages, and promotes replication of M. tuberculosis in macrophages. Also it is known thatmutations in CpnT appear to be associated with increased drug resistance in M. tuberculosis.Results for M. bovis BCG and the resistant strains of M. tuberculosis indicate that the three dominantfactors governing drug efficacy are the excitation energy of the first excited state, the HOMO-LUMOgap, and the lipophilicity of the drugs. It can be concluded that MICs are negatively related to theexcitation energy, positively related to the HOMO-LUMO gap, and negatively related to the lipophilicityof the drugs. The ion channels of resistant forms of these bacteria can be targeted by an appropriateselection of drugs using these three factors to design appropriate inhibitors or antibiotics. Ion channelinhibitors can act as synergistic adjuvants to tuberculosis antibiotics.Based on the notion that the commonly used anti-tuberculosis drugs isoniazid, pyrazinamide andethambutol target the outer membrane of M. tuberculosis, a study of the cucurbit[7]uril inclusioncomplexes isoniazid@CB[7], pyrazinamide@CB[7], and ethambutol@CB[7] shows that these complexeshave enhanced lipophilicity over that for the naked antibiotics, as well as enhanced potency. Suchproperties may offer increased anti-tuberculosis potency compared to the naked antibiotics, as well asoffer reduced metabolic degradation, oral administration, and increased solubility of such drugs asroutinely associated with inclusion complexes.Ethambutol@CB[7] is known to be as efficient in treating M. smegmatis infected macrophages asopposed to when it was delivered in the unbound form, suggesting that CB[7]-bound drug molecules canbe released from the container to find their intracellular target and to be effective in macrophages. Studiesof (a) isoniazid@CB[7] and its free radical intermediate isoniazid acyl radical@CB[7], (b) the prodrugpyrazinamide@CB[7] and its active species pyrazinoic acid@CB[7], indicate that these reactiveintermediates may offer enhanced anti-tuberculosis activity over that for the normal inclusion complexes. |
| Databáze: | OpenAIRE |
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