Viewpoint Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Novel Modifications of Glycopeptide Antibiotics via Total Synthesis David J. Newman* Newman Consulting LLC, Wayne, Pennsylvania 19087, United States ABSTRACT: Although vancomycin has been in clinical use since the late 1950s, resistance due to alteration in the target microbe’s peptidoglycan can vary significantly, reducing its activity. Total synthesis of derivatives has now led to a molecule with very significant activity against resistant strains.
I
n early 2017, the World Health Organization listed 12 microbes that were of “major concern” as they were all resistant to significant numbers of antibiotics that were in current use at the time. Of the dozen microbes, the first three, denoted as priority 1 and listed as critical, were all Gramnegative organisms, but the next six, with a priority of 2 and listed as high, included two very well-known Gram-positive pathogens, Enterococcus faecium and Staphylococcus aureus. Both of these pathogens had resistance to vancomycin and, in the case of Staphylococcus aureus, resistance to methicillin (hence the MRSA abbreviation). Vancomycin was introduced into antibiotic treatment in 1955 by Lilly, so it could be considered one of the early treatments against Gram-positive human pathogens. Unlike the early penicillins, however, it had to be delivered parenterally, so it was used in a hospital setting rather than as an outpatient procedure. It was not until 20 years after its introduction, that the full structure was known, when in 1982, Harris and Harris1 correctly identified an asparagine residue in the antibiotic, leading to the structure shown (1) in Figure 1. Due to its method of delivery as mentioned above, it was usually kept as the “antibiotic of last resort”, particularly with the rise of MRSA infections beginning in late 1960 in the UK and then worldwide by the middle 1960s. A very informative article was recently published by Harkins et al.2 indicating that the resistance gene product (PBP2a) in MRSA existed in samples collected before methicillin was used in a clinical setting and may well have been induced by the earliest penicillins. However, although one could use vancomycin against MRSA infections, S. aureus strains arose that were resistant to vancomycin as well as being formally “MRSA”. Vancomycin acts by binding the terminal amino acid residues l-Lys-d-Ala-dAla-CO2H within the cyclic peptide portion of the molecule (cf 1). The major resistance phenotypes had subtle changes in their terminal tripeptide, with the vanA, vanB, and vanD phenotypes © XXXX American Chemical Society
Figure 1. Vancomycin and Boger group substitutions.
substituting a d-Lac for the final d-Ala and the vanC, vanE, and vanG phenotypes substituting d-Ser. The rise of the vancomycin-resistance phenotypes in clinical practice was such that new antibiotics were required to deal with it as one now had a significant increase in infections where the microbe was both methicillin and vancomycin resistant. The d-Lac modification caused approximately a 1000-fold increase in resistance with the d-Ser modification being approximately 7-fold less sensitive. Initially the increased used of glycopeptide antibiotics in animal feeds was thought to be a
A
DOI: 10.1021/acsmedchemlett.8b00029 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
■
potential cause of increased resistance, but work by D’Costa et al.3 indicated that these resistance genes were seen in microbial extracts from Arctic sources that were >10,000 years old, which does raise an interesting point regarding MRSA resistance as the work referred to earlier only investigated UK clinical isolates from around 1960. From roughly 1960, a number of other glycopeptide antibiotics were introduced into clinical use in Europe and the USA. Structures are not given due to the restrictions on number of figures, but ristocetin entered use in the 1960s in Europe but was later withdrawn due to platelet aggregation. Teicoplanin was introduced in Italy in 1988, and it also has an oral formulation but is not approved in the USA; however, it does have activity against vanB. Three others have been approved for use in the USA, frequently after very protracted clinical trials under a number of companies. Thus, telavancin, derived from a semisynthetic modification of vancomycin was approved in 2009, with dalvabancin (derived from a teicoplanin-like component of the A40926 complex) approved in 2014, followed later in the same year by oritavancin (derived from chloroeremomycin). However, in the past few years, the Boger group at the Scripps Research Institute in La Jolla, California, has built upon earlier work on the total synthesis of very interesting and active variations on the base vancomycin structure.4−6 These reports followed on from earlier work covering a ristocetin aglycone total synthesis.7 Quite recently, his group reported the synthesis of a chlorobiphenyl derivative of vancomycin (as found in oritavancin) plus the addition of an alkylammonium side chain on the second ring structure of vancomycin (as in dalbavancin). This compound together with close relatives where the length of the alkyl chain was altered exhibited good antimicrobial activity against microbes with the vanA phenotype, with activities being between 100 and 1000 times more potent.8 However, the major change, permitting increased membrane permeability coupled to maintenance of excellent antimicrobial activities, was the conversion of one amide carbonyl group in the tripeptide binding pocket to a methylene yielding structure (2) in Figure 1. This compound maintained activity against both d-Ala-d-Ala and d-Ala-d-Lac end groups. In addition, it exhibited no significant increase in resistance after 25 passages. The full details are given in three excellent reports that should be consulted in order to see the methodologies used for such work.8−10 Since clinical isolates that are resistant to colistin (aka polymyxin) have now been reported to occur in man11 and this compound was considered to be an antibiotic of last resort, then further development of the Boger “vancomycin derivative” and related molecules will definitely be of interest. In addition, as demonstrated in the recent paper by Yang et al.12 there is also the potential for synthesis of some simpler vancomycin-like derivatives.
■
Viewpoint
REFERENCES
(1) Harris, C. M.; Harris, T. M. Structure of the glycopeptide antibiotic vancomycin. Evidence for an asparagine residue in the peptide. J. Am. Chem. Soc. 1982, 104, 4293−4295. (2) Harkins, C. P.; Pichon, B.; Doumith, M.; Parkhill, J.; Westh, H.; Tomaz, A.; de Lencastre, H.; Bentley, S. D.; Kearns, A. M.; Holden, M. T. G. Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. Genome Biol. 2017, 18, 130. (3) D’Costa, V. M.; King, C. E.; Kalan, L.; Morar, M.; Sung, W. W. L.; Schwartz, C.; Froese, D.; Zazula, G.; Calmels, F.; Debruyne, R.; Golding, G. B.; Poinar, H. N.; Wright, G. D. Antibiotic resistance is ancient. Nature 2011, 477, 457−461. (4) Xie, J.; Pierce, J. G.; James, R. C.; Okano, A.; Boger, D. L. A redesigned vancomycin engineered for dual D-Ala-D-Ala and D-Aal-DLac binding exhibits potent antimicrobial activity against vancomycinresistant bacteria. J. Am. Chem. Soc. 2011, 133, 13946−13949. (5) Okano, A.; Nakayama, A.; Schammel, A. W.; Boger, D. L. Total syntheses and initial evaluation of [Ψ[CNH)NH]Tpg4]vancomycin and its (4-chlorobiphenyl)methyl derivative: Impact of peripheral modifications on vancomycin analogues redesigned for dual D-Ala-DAla and D-Ala-D-Lac binding. J. Am. Chem. Soc. 2014, 136, 13522− 13525. (6) Okano, A.; Nakayama, A.; Wu, K.; Lindsey, E. A.; Schammel, A. W.; Feng, Y.; Collins, K. C.; Boger, D. L. Total syntheses and initial evaluation of [Ψ[CS)NH]Tpg4]vancomycin, [Ψ[CNH)NH]Tpg4] vancomycin, [Ψ[CH2NH]Tpg4]vancomycin and their (4chlorobiphenyl)methyl derivatives: Synergistic binding pocket and peripheral modifications for the glycopeptide antibiotics. J. Am. Chem. Soc. 2015, 137, 3693−3704. (7) Crowley, B. M.; Mori, Y.; McComas, C. C.; Tang, D.; Boger, D. L. Total synthesis of the ristocetin aglycon. J. Am. Chem. Soc. 2004, 126, 4310−4317. (8) Okano, A.; Isley, N. A.; Boger, D. L. Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. Proc. Natl. Acad. Sci. U. S. A. 2017, 82, E5052−E5061. (9) Okano, A.; Isley, N. A.; Boger, D. L. Total syntheses of vancomycin-related glycopeptide antibiotics and key analogues. Chem. Rev. 2017, 117, 11952−11993. (10) Boger, D. L. The difference a single atom can make: Synthesis and design at the chemistry-biology interface. J. Org. Chem. 2017, 82, 11961−11980. (11) Liu, Y.-Y.; Wang, Y.; Walsh, T. R.; Yi, L.-X.; Zhang, R.; Spencer, J.; Doi, Y.; Tian, G.; Dong, B.; Huang, X.; Yu, L.-F.; Gu, D.; Ren, H.; Chen, X.; Lv, L.; He, D.; Zhou, H.; Liang, Z.; Liu, J.-H. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: A microbiological and molecular biological study. Lancet Infect. Dis. 2016, 16, 161−168. (12) Yang, X.; Beroske, L. P.; Kemmink, J.; Rijkers, D. T. S.; Liskamp, R. M. J. Synthesis of bicyclic tripeptides inspired by the ABC-Ring system of vancomycin through ruthenium-based cyclization chemistries. Tetrahedron Lett. 2017, 58, 4542−4546.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Funding
Self-funded Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS. The author declares no competing financial interest. B
DOI: 10.1021/acsmedchemlett.8b00029 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
