ent-Beyerane Diterpenes as a Key Platform for the Development of ArnT-Mediated Colistin Resistance Inhibitors

Abstract

Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent -beyerene diterpene was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy- l -arabinose arabinosyl transferase). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent -beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent -beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.

A unique high-diversity natural product collection as a reservoir of new therapeutic leads

“…In the latter approach in particular, computational screening was useful for identifying a diterpene lead, which was subsequently optimized up to the development of more accessible semi-synthetic ent-beyerane diterpenes as valuable and cost-effective colistin resistance inhibitors with a potential translational impact (see section 4.5). 69,101,102 Overall, computational approaches facilitated the placement of multiple chemotypes of natural products as hits/ leads for pharmacological application. Notwithstanding the relatively limited dimensions of the in house library, no overlap between the scaffolds of bioactive compounds was observed using the approaches outlined in this review, which suggests that enhancing the chemical diversity of a compounds library might have a more powerful effect than increasing its size.…”

“…The ent-beyerane skeleton, which differs from the parental ent-beyerene scaffold in that it lacks unsaturation between C-15 and C-16 and has an absolute configuration at C-4 (R rather than S), was identified for the first time as a privileged scaffold for further development and optimization of valuable colistin resistance inhibitors. 102,170 Triterpenes have relatively complex cyclic structures, most of them being alcohols, aldehydes, or carboxylic acids, and represent the largest class of terpenes in the in house library, including friedlane, oleane, ursane, lupan, and steroid types. Triterpenes exhibit a spectrum of important pharmacological activities, and quinone-methide triterpenes in particular, which have been extensively studied over the last few decades, were found to inhibit CSCs that are resistant to standard chemotherapies.…”

How to Combat Gram-Negative Bacteria Using Antimicrobial Peptides: A Challenge or an Unattainable Goal?

“…For example, 4′-phosphate (negatively charged) in lipid A is replaced by 4-amino-4-deoxy-L-arabinopyranose (L-Arap4N) (positively charged) in an ArnT-mediated process or ethanolamine molecules (positively charged) are added to the diphosphates (negatively charged) in an EptB-mediated process; these changes lead to electrostatic repulsion with cationic AMP amino acids thereby making bacteria resistant to AMPs ( Figure 2 ) [ 65 , 69 ]. Such changes explain why AMPs like polymyxin B are less active against species such as Proteus mirabilis which usually has less negatively charged LPS than most E. coli strains [ 65 ] or why some E. coli , Klebsiella pneumoniae or P. aeruginosa strains are resistant and others sensitive to polymyxins-B or -E [ 69 , 70 , 71 ].…”

Identification of Effective Anticancer G-Quadruplex-Targeting Chemotypes through the Exploration of a High Diversity Library of Natural Compounds

“…During the years, the exploitation of this in-house collection of natural products offered a unique chance to identify unexpected new scaffolds for the development of therapeutically relevant molecules. Furthermore, the successful application of computer-aided methods in screening this unique and diverse in-house library provided some lead compounds that have been developed and, in some cases, patented as anticancer and antimicrobial agents [24][25][26][27][28]. Here, a docking-based virtual screening has been carried out, using both telomeric and oncogenic G4 models as targets [29,30], to evaluate the ability of the in-house natural products to target G4 grooves and identify novel G4-targeting chemotypes.…”