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Gram-Scale Total Synthesis of Teixobactin Promoting Binding Mode Study and Discovery of More Potent Antibiotics

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Gram-Scale Total Synthesis of Teixobactin Promoting Binding Mode Study and Discovery of More Potent Antibiotics ARTICLE https://doi.org/10.1038/s41467-019-11211-y OPEN Gram-scale total synthesis of teixobactin promoting binding mode study and discovery of more potent antibiotics Yu Zong1,5, Fang Fang1,5, Kirsten J. Meyer2, Liguo Wang1, Zhihao Ni1, Hongying Gao3, Kim Lewis2, Jingren Zhang4 & Yu Rao1 1234567890():,; Teixobactin represents a new class of antibiotics with novel structure and excellent activity against Gram-positive pathogens and Mycobacterium tuberculosis. Herein, we report a one-pot reaction to conveniently construct the key building block L-allo-Enduracidine in 30-gram scale in just one hour and a convergent strategy (3 + 2 + 6) to accomplish a gram-scale total synthesis of teixobactin. Several analogs are described, with 20 and 26 identified as the most efficacious analogs with 3~8-fold and 2~4-fold greater potency against vancomycin resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus respectively in comparison with teixobactin. In addition, they show high efficiency in Streptococcus pneumoniae septicemia mouse model and neutropenic mouse thigh infection model using methicillin-resistant Sta- phylococcus aureus. We also propose that the antiparallel β-sheet of teixobactin is important for its bioactivity and an antiparallel dimer of teixobactin is the minimal binding unit for lipid II via key amino acids variations and molecular docking. 1 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 100084 Beijing, China. 2 Antimicrobial Discovery Center, Northeastern University, Department of Biology, Boston, MA 02115, USA. 3 Tsinghua-Peking Center for Life Sciences, Haidian District, 100084 Beijing, China. 4 Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China. 5These authors contributed equally: Yu Zong, Fang Fang. Correspondence and requests for materials should be addressed to Y.R. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:3268 | https://doi.org/10.1038/s41467-019-11211-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-11211-y ntibiotic resistance becomes a rapidly growing health scale and a convergent strategy to achieve gram-scale synthesis of – Aconcern and poses great challenge for the human1 3.In teixobactin. A series of analogs retaining L-allo-End are synthe- the postantibiotic era, people may die from ordinary sized and more potent candidates are discovered. Finally, a infections and minor injuries due to a lack of effective antibiotics, detailed binding model in which the antiparallel dimer of teix- so novel antibacterial lead structures are urgently needed for obactin is the minimal binding unit for lipid II and the anti- guaranteeing future therapeutic efficacy. Recently, a new anti- parallel β-sheet of teixobactin is important for its bioactivity is biotic named teixobactin was reported by Lewis and coworkers, raised via key amino acids variations and docking. and it exhibits excellent bioactivities against Gram-positive pathogens and Mycobacterium tuberculosis4. Given that teix- obactin targets conserved substrates (Lipid II and III) rather than Results and discussion enzymes in peptidoglycan and teichoic acid biosynthetic path- Retrosynthetic analysis of teixobactin. Initially, we attempted to ways, the emergence of resistance is expected to be difficult, accomplish the total synthesis of teixobactin in a convergent which makes teixobactin a promising candidate for further drug synthetic route in which we could readily change any amino acids development5. to access teixobactin analogs without resorting to de novo Teixobactin contains a nonnatural amino acid L-allo-End synthesis in global SPPS. Simultaneously, drawing lessons from possessing a unique cyclic guanidine moiety, which exists in other our previous procedure of yielding a series of teixobactin analogs natural products, such as mannopeptimycin and enduracidins6,7. by combining solution-phase with solid-phase synthesis, we pro- However, the presence of the unnatural amino acid L-allo-End posed that teixobactin could also be derived from a cyclic penta- complicates its total synthesis as reflected in several endeavors peptide and a linear hexapeptide which could be constructed in from the Payne8,Li9, and Chen10 groups. They achieved the solution-phase and solid-phase, respectively (“5 + 6”)18. During milligram scale total synthesis of teixobactin. Payne reported the the removal of Fmoc of L-allo-End residue in SPPS, the generated first total synthesis of teixobactin in global solid-phase peptide free α-amine could attack the adjacent α-carboxyl of L-isoleucine synthesis (SPPS). Simultaneously, Li presented an elegant total to form unwanted DKP readily8. To avert this by-product, synthesis of teixobactin using Ser/Thr ligation. Chen achieved a dipeptide of Alloc-Ala-allo-End-OH was considered as an integral synthesis with a linear synthetic procedure recently. Despite these unit in the synthesis of cyclic pentapeptide. In addition, as ester impressive developments, scalable synthesis of teixobactin has condensation between Ile and secondary OH group of D-Thr in remained elusive, because of the tedious synthesis of L-allo-End SPPS led to 33% epimerization19, we intended to achieve the and generation of diketopiperazine (DKP) by-product in SPPS8 esterification in solution phase to exclude this side product. So (Fig. 1). On the other hand, the L-allo-End seems to be important the cyclic pentapeptide could be divided into dipeptide and for biological activity. When L-allo-End was replaced by Arg or tripeptide (“2 + 3”) (Fig. 1). Lys, it led to about fourfold loss of potency11–15. So far, by replacement of L-allo-End and modifications on other amino acids, only Singh and our group reported analogs with equal Synthesis of L-allo-End building block. Presently, there are three 16–18 potency to teixobactin . However, it was a pity that any original routes to approach L-allo-End. Du Bois group used bioactivity of analogs retaining L-allo-End has not been reported. rhodium catalyst to provide racemic End from compound 120. Therefore, further probing the structure-activity relationship of Payne group constructed L-allo-End in seven steps from Boc-Asp- teixobactin analogs retaining L-allo-End to gain stronger anti- OtBu (compound 2)8. The Yuan group built L-allo-End in ten biotics is valuable. Herein, we demonstrate a one-pot reaction to steps from hydroxyproline (compound 3) in 31% overall yield21 conveniently construct the key L-allo-End building block in 30-g (Fig. 2). We sought a more concise synthetic strategy for L-allo-End10 IIe11 Challenges: 1. Relatively complicated D-Gln4 Challenge 3 for scalable synthesis IIe2 IIe6 D-Thr8 Challenge 1 2. Prone to diketopiperazine formation in SPPS Challenge 2 3. Epimerization (2:1) in SPPS Ala9 Ser3 Ser7 D-allo-IIe5 '5 + 6' D-NMe-Phe1 '2 + 3' TrtHN Diketopiperazine + Dipeptide as one unit: averting DKP formation Solid-phase peptide synthesis (SPPS) Lactamization Solution-phase peptide synthesis Fig. 1 Current challenges and retrosynthetic analysis of teixobactin. There are three challenges in scalable total synthesis of teixobactin. Teixobactin could be synthesized via the convergent strategy (3 + 2 + 6) 2 NATURE COMMUNICATIONS | (2019) 10:3268 | https://doi.org/10.1038/s41467-019-11211-y | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-11211-y ARTICLE Du bois group Payne group Rh 17% 7 steps 4S/4R = 1/1, 1 2 3 steps, 10% R1 = Fmoc, R2 = R3 = Cbz, R4 = H R1–4 = H End Our synthetic route 66%, one-pot, 1h R1 = Fmoc, R2 = Cbz, R3 = H, R4 = Me 31% Our strategy 10 steps R1–4 = H Yuan group 4 Intermediate 5 3 Fig. 2 Synthetic strategy to L-allo-enduracididine. There are three reported routes to provide End. Our synthetic route just takes 1 h via a one-pot reaction to synthesize desired End Table 1 Identification of optimal reagents for constructing L-allo-End O R N NR NH O 2 O 1 Steric O hindrance N NH R HN N HN H AcOH:MeOH 2 Conditions R1N HN O H /1:9,RT,15 min NR1 NR O N O H 2 N O 4 NOE O 6a R1 = Phth, R2 = Boc; N HN H Intermediate 5 6b R1 = Fmoc, R2 = Cbz; 6c R1 = Boc, R2 = Cbz H Entry Conditions Yield a 1 10% Pd(OAc)2, 2 equiv. CuCl2, 2 equiv. NaHCO3, MeCN, RT, 1 h 5% 2a 3 equiv. tBuOCl, DCM, RT, 2 h <5% a 3 2 equiv. NIS, 4 equiv. NaHCO3, MeCN, 0 °C, 0.5 h 52% (dr 5:1) a 4 3 equiv. I2, 4 equiv. NaHCO3, MeCN, RT, 1 h 56% a 5 3 equiv. I2, 4 equiv. NaHCO3, MeCN, 0 °C, 1 h 65% (dr 5:1) b 6 3 equiv. I2, 4 equiv. NaHCO3, THF, 0 °C, 1 h 71% (dr > 15:1) c 7 3 equiv. I2, 4 equiv. NaHCO3, MeCN, 0 °C, 1 h 61% (dr > 15:1) a R1 = Phth, R2 = Boc b R1 = Fmoc, R2 = Cbz c R1 = Boc, R2 = Cbz providing adequate L-allo-End to simplify the total synthesis of separated in 71% and 61% yield, respectively with excellent teixobactin and promote potential clinical applications. stereoselectivity (dr > 15:1) (entries 6 and 7). Arising from the Inspired by inter- and intramolecular diamination and instability of intermediate 5, alcoholysis occurred readily to guanidinylation22–26 of alkenes, we proposed a cascade reaction furnish desired compound 6. It just took 1 h for this one-pot in which intramolecular guanidinylation of compound 4 occurred reaction to access protected L-allo-End (Table 1) to generate intermediate 5, followed by alcoholysis of the amide As intermediate 5a was not separable for its instability, the bond to access protected L-allo-End (Fig. 2). Our design required relatively stable compound 7 without Boc was separated and preinstalled guanidine at C-terminal via Bop-mediated amide confirmed through nuclear magnetic resonance (NMR) analysis.
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