Kanglemycin A
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| Category | Antibiotics |
| Catalog number | BBF-03751 |
| CAS | 114153-91-2 |
| Molecular Weight | 982.03 |
| Molecular Formula | C50H63NO19 |
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Description
Kanglemycin A (KglA) is related to rifampicin, an antibiotic that functions by binding to bacterial RNA polymerase. KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis.
Specification
| Synonyms | Antibiotic 1747; Rifamycin, 20-(1-(3-carboxy-2,2-dimethyl-1-oxopropoxy)ethyl)-20-demethyl-27-O-demethyl-1,4-dideoxy-27-O-(2,6-dideoxy-3,4-O-methylene-beta-D-ribo-hexopyranosyl)-1,4-dihydro-1,4-dioxo-; Kanglemeisu A; KglA |
| IUPAC Name | 4-[(1S)-1-[(7S,9E,11S,12R,13S,14R,15R,16S,17R,18S,19E,21Z)-11-[[(3aR,4R,6R,7aS)-4-methyl-4,6,7,7a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl]oxy]-13-acetyloxy-2,15,17-trihydroxy-3,7,12,14,16,22-hexamethyl-6,23,27,29-tetraoxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25-heptaen-18-yl]ethoxy]-3,3-dimethyl-4-oxobutanoic acid |
| Canonical SMILES | CC1C(C=COC2(C(=O)C3=C(O2)C(=C(C4=C3C(=O)C=C(C4=O)NC(=O)C(=CC=CC(C(C(C(C(C1OC(=O)C)C)O)C)O)C(C)OC(=O)C(C)(C)CC(=O)O)C)O)C)C)OC5CC6C(C(O5)C)OCO6 |
| InChI | InChI=1S/C50H63NO19/c1-21-13-12-14-29(26(6)67-48(62)49(9,10)19-34(54)55)40(57)23(3)39(56)24(4)43(68-28(8)52)22(2)32(69-35-18-33-45(27(7)66-35)64-20-63-33)15-16-65-50(11)46(60)38-36-31(53)17-30(51-47(21)61)42(59)37(36)41(58)25(5)44(38)70-50/h12-17,22-24,26-27,29,32-33,35,39-40,43,45,56-58H,18-20H2,1-11H3,(H,51,61)(H,54,55)/b14-12+,16-15+,21-13-/t22-,23+,24-,26+,27-,29-,32+,33+,35+,39-,40-,43-,45-,50+/m1/s1 |
| InChI Key | KRBOMQKIXLJMRA-JVZUHZKESA-N |
Properties
| Antibiotic Activity Spectrum | Gram-positive bacteria; Mycobacteria |
| Boiling Point | 1112.5°C at 760 mmHg |
| Density | 1.38 g/cm3 |
Reference Reading
1. Synthesis and evaluation of dual-action kanglemycin-fluoroquinolone hybrid antibiotics
James Peek, Bimal Koirala, Sean F Brady Bioorg Med Chem Lett. 2022 Feb 1;57:128484. doi: 10.1016/j.bmcl.2021.128484. Epub 2021 Nov 30.
Bacterial resistance threatens the utility of currently available antibiotics. Rifampicin, a cornerstone in the treatment of persistent Gram-positive infections, is prone to the development of resistance resulting from single point mutations in the antibiotic's target, RNA polymerase. One strategy to circumvent resistance is the use of 'hybrid' antibiotics consisting of two covalently linked antibiotic entities. These compounds generally have two distinct cellular targets, reducing the probability of resistance development and potentially providing simplified pharmacological properties compared to combination therapies using the individual antibiotics. Here we evaluate a series of semi-synthetic hybrid antibiotics formed by linking kanglemycin A (Kang A), a rifampicin analog, and a collection of fluoroquinolones. Kang A is a natural product antibiotic which contains a novel dimethyl succinic acid moiety that offers a new attachment point for the synthesis of hybrid antibiotics. We compare the activity of the Kang A hybrids generated via the acid attachment point to a series of hybrids linked at the compound's naphthoquinone ring system. Several hybrids exhibit activity against bacteria resistant to Kang A via the action of the partnered antibiotic, suggesting that the Kang scaffold may provide new avenues for generating antibiotics effective against drug-resistant infections.
2. Kanglemycin A Can Overcome Rifamycin Resistance Caused by ADP-Ribosylation by Arr Protein
John Harbottle, Hamed Mosaei, Nicholas Allenby, Nikolay Zenkin Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0086421. doi: 10.1128/AAC.00864-21. Epub 2021 Oct 4.
Rifamycins, such as rifampicin (Rif), are potent inhibitors of bacterial RNA polymerase (RNAP) and are widely used antibiotics. Rifamycin resistance is usually associated with mutations in RNAP that preclude rifamycin binding. However, some bacteria have a type of ADP-ribosyl transferases, Arr, which ADP-ribosylate rifamycin molecules, thus inactivating their antimicrobial activity. Here, we directly show that ADP-ribosylation abolishes inhibition of transcription by rifampicin, the most widely used rifamycin antibiotic. We also show that a natural rifamycin, kanglemycin A (KglA), which has a unique sugar moiety at the ansa chain close to the Arr modification site, does not bind to Arr from Mycobacterium smegmatis and thus is not susceptible to inactivation. We, found, however, that kanglemycin A can still be ADP-ribosylated by the Arr of an emerging pathogen, Mycobacterium abscessus. Interestingly, the only part of Arr that exhibits no homology between the species is the part that sterically clashes with the sugar moiety of kanglemycin A in M. smegmatis Arr. This suggests that M. abscessus has encountered KglA or rifamycin with a similar sugar modification in the course of evolution. The results show that KglA could be an effective antimicrobial against some of the Arr-encoding bacteria.
3. Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism
James Peek, Mirjana Lilic, Daniel Montiel, Aleksandr Milshteyn, Ian Woodworth, John B Biggins, Melinda A Ternei, Paula Y Calle, Michael Danziger, Thulasi Warrier, Kohta Saito, Nathaniel Braffman, Allison Fay, Michael S Glickman, Seth A Darst, Elizabeth A Campbell, Sean F Brady Nat Commun. 2018 Oct 8;9(1):4147. doi: 10.1038/s41467-018-06587-2.
Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (RifR). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant RifR mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of RifR RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms.
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Bio Calculators
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
* Total Molecular Weight:
g/mol
Tip: Chemical formula is case sensitive. C22H30N4O √ c22h30n40 ╳
