Development of teixobactin analogues containing hydrophobic, non-proteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms
Parmar, Anish; Lakshminarayanan, Rajamani; Iyer, Abhishek; Goh, Eunice Tze Leng; To, Tsz Ying; Yam, Joey Kuok Hoong; Yang, Liang; Newire, Enas; Robertson, Maria C.; Prior, Stephen H.; Breukink, Eefjan; Madder, Annemieke; Singh, Ishwar
(2023) European Journal of Medicinal Chemistry, volume 261, pp. 1 - 12
(Article)
Abstract
Teixobactin is a cyclic undecadepsipeptide that has shown excellent potency against multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). In this article, we present the design, synthesis, and antibacterial evaluations of 16 different teixobactin analogues. These simplified analogues contain commercially available hydrophobic, non-proteogenic amino acid residues
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instead of synthetically challenging expensive L-allo-enduracididine amino acid residue at position 10 together with different combinations of arginines at positions 3, 4 and 9. The new teixobactin analogues showed potent antibacterial activity against a broad panel of Gram-positive bacteria, including MRSA and VRE strains. Our work also presents the first demonstration of the potent antibiofilm activity of teixobactin analogoues against Staphylococcus species associated with serious chronic infections. Our results suggest that the use of hydrophobic, non-proteogenic amino acids at position 10 in combination with arginine at positions 3, 4 and 9 holds the key to synthesising a new generation of highly potent teixobactin analogues to tackle resistant bacterial infections and biofilms.
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Keywords: Antibiofilm, Antimicrobial resistance, Biofilms, MRSA, Teixobactin, VRE, Taverne, Pharmacology, Drug Discovery, Organic Chemistry
ISSN: 0223-5234
Publisher: Elsevier Masson SAS
Note: Funding Information: The antibacterial properties of the synthesised teixobactin analogues were investigated against a panel of 16 Gram-positive strains, such as MRSA, VRE (Table 1). To gain better insight into the structure–activity relationship, we determined the geometric mean MIC (GM-MIC) values for all teixobactin analogues and compared the results. A clear correlation between the number of carbons in the sidechain at position 10 and GM-MIC was observed (Fig. 3a). The best overall results were obtained for compounds containing a Chg10 substitution (compounds 1–8), which showed highly potent antibacterial activity against all bacteria tested with MIC values in the range of 0.0625–0.125 μg/mL and a GM-MIC of 0.07 μg/mL. Thus, natural or unnatural residues carrying bulky side chains of ≥4 carbons (Chg or Ile/Leu) at position 10 resulted in the lowest GM-MIC values (Fig. 3a). This was further supported by the fact that substitution of residues containing linear alkyl groups (Nle) (16) resulted in 2-fold higher GM-MIC values than Ile10-teixobactin (18). Among the amino acids containing isopropyl or n-propyl (Val or Nva) side chains at position 10; Val10-teixobactin [14] had a two-fold higher GM-MIC than Nva10-teixobactin (9). Next, we investigated the importance of the overall net charge of the teixobactin analogues on GM-MIC values. In particular, we focused our attention on the substitution of L-Arg residues at positions 3 and 9 and D-Arg at position 4 in Chg10-texiobactin and Nva10-teixobactin. The results indicated that substitution with cationic residues at all three positions did not affect the GM-MIC values for Chg10 and Nva10 teixobactin analogues. These results are consistent with the results obtained for Leu10-teixobactin (Fig. 3b). However, the substitution of L-Arg at position 3 or 9 increased the GM-MIC values for Ile10-teixobactin, suggesting that Chg10/Nva10-teixobactin analogues have broader scopes for the substitution of cationic residues.Ishwar Singh acknowledges the Innovate UK and Department of Health and Social Care (DHSC), UK and Rosetrees Trust for their kind support (SBRI grant 106368-623146 and Rosetrees Trust grant CF-2021-2\102). The views expressed in this publication are those of the authors and not necessarily those of Innovate UK or DHSC, UK. Rajamani Lakshminarayanan would like to acknowledge funding support from the Singapore Ministry of Health's National Medical Research Council under its Centre Grant Programme – Optimisation of Core Platform Technologies for Ocular Research (INCEPTOR)-NMRC/CG/M010/2017_SERI. Funding Information: Ishwar Singh acknowledges the Innovate UK and Department of Health and Social Care (DHSC), UK and Rosetrees Trust for their kind support ( SBRI grant 106368-623146 and Rosetrees Trust grant CF-2021-2\102 ). The views expressed in this publication are those of the authors and not necessarily those of Innovate UK or DHSC, UK. Rajamani Lakshminarayanan would like to acknowledge funding support from the Singapore Ministry of Health's National Medical Research Council under its Centre Grant Programme – Optimisation of Core Platform Technologies for Ocular Research (INCEPTOR)-NMRC/CG/M010/2017_SERI. Publisher Copyright: © 2023 Elsevier Masson SAS
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