Convergent Synthesis of Calcium-Dependent Antibiotic CDA3a and Analogues with Improved Antibacterial Activity via Late-Stage Serine Ligation

Article abstract of DOI:10.1021/acs.orglett.0c01544

A convergent synthesis via the late-stage serine ligation of naturally occurring calcium-dependent antibiotic CDA3a and its analogues has been developed, which allowed us to readily synthesize the analogues with the variation on the lipid tail. Some analogues were found to show 100-500-fold higher antimicrobial activity than the natural compound CDA3a against drug resistant bacteria. This study will enhance our understanding of CDA3a and provide valuable antibacterial lead candidates for further development.

Full text of DOI:10.1021/acs.orglett.0c01544

pubs.acs.org/OrgLett
Letter
Convergent Synthesis of Calcium-Dependent Antibiotic CDA3a and
Analogues with Improved Antibacterial Activity via Late-Stage
Serine Ligation
Delin Chen, Kathy Hiu Laam Po, Pilar Blasco, Sheng Chen, and Xuechen Li*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c01544
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A convergent synthesis via the late-stage serine ligation of naturally occurring calcium-dependent antibiotic CDA3a
and its analogues has been developed, which allowed us to readily synthesize the analogues with the variation on the lipid tail. Some
analogues were found to show 100−500-fold higher antimicrobial activity than the natural compound CDA3a against drug resistant
bacteria. This study will enhance our understanding of CDA3a and provide valuable antibacterial lead candidates for further
development.
he rapid emergence of widespread bacterial resistance to
Texisting antibacterial drugs has become an urgent global
threat to human health, which calls for the development of new
antibiotics.1 Cyclic peptides have been an important class of
modalities as antibacterial agents,2 such as vancomycin,
bacitracin, colistin/polymyxin, gramicidin, and daptomycin,
all being clinically used. New cyclic peptides with promising
antibacterial profiles have been discovered in recent years,
including teixobactin,3 malacidins,4 cadaside,5 and darobactin,6
which hold promise for future clinical applications. Among all
these antibacterial cyclic peptides, daptomycin,7,8 A54145,9,10
malacidins,11 and cadaside12 are grouped into calcium
dependent antibiotics, which require the Ca2+ in serum to
exert their antibacterial acts. They contain a distinct calcium
binding motif (Asp-Xaa-Asp-Gly) responsible for calcium
binding.13,14
Figure 1. Structures of CDA3a and its congeners.
the specific amino acid residues, and none of the generated
analogues showed comparable or improved antibacterial
activity compared to the natural compound. Chemical
synthesis would promise to overcome the bioengineering
limitation in generating analogues; however, the total synthesis
of CDAs has not been reported yet.
The calcium-dependent antibiotics (CDAs)15−17 were first
extracted from Streptomyces coelicolor A3(2) (Figure 1). It
comprises an exocyclic tail containing a serine and N-terminal
fatty acid side chain (a trans-2,3-epoxyhexanoyl moiety), along
with a cyclic decadepsipeptide. Based on the complete genome
sequence of CDAs’ producer Streptomyces coelicolor A3, the
biosynthesis of CDAs has been established and later
engineered to produce CDAs’ analogues.18−27 Due to
bioengineering restrictions, the modifications were limited to
Received: May 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01544
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
CDA3a features an unusual trans-2,3-epoxyhexanoyl exocy-
clic tail, together with three nonproteinogenic amino acid
residues including Z-dehydrotryptophan at position 11, D-4-
hydroxyphenylglycine (D-Hpg) at position 6, and (2R,3S)-3-
hydroxyasparagine (3-HOAsn) at position 9.15−17 The notable
structural motif is the Z-dehydrotryptophan residue. The
planar geometry at α,β-carbons of Z-dehydrotryptophan
profoundly reduces the conformational flexibility of CDA3a,
which can also confer resistance to enzymatic degradation and
alter bioactivity.28,29 Dehydrotryptophan is found in many
natural products.29 The syntheses of several dehydrotrypto-
phan amino acid and dipeptide derivatives have been
reported;29 however, the total synthesis of dehydrotrypto-
phan-containing large peptides is yet to be developed.
Prompted by its unique structural features, antibacterial
activity, and availability of the high-quantity NMR spectrum,
we set out to develop the total synthesis of CDA3a, which
further enables us to carry out the structure−activity
relationship studies to develop analogues with improved
antibacterial profiles.
Scheme 1. Unsuccessful Routes Towards Tripeptide 4
to the new strategy, the carboxylic acid of 5 was first protected
with allyl, followed by Boc deprotection and amine
reprotection with phthalimide. The obtained 9 was subjected
to the direct dehydrogenation to provide the corresponding
product 10 in 88% yield as a single Z-isomer which is
thermodynamically more stable than the E-isomer.29 Then,
removal of the N-Phth group and treatment with freshly
prepared glutamic acid anhydride were followed by depro-
tection of the allyl group to afford the carboxylic acid.
Unfortunately, esterification of 11 failed under a variety of
attempted conditions. Apparently, the unsaturation dramati-
cally deactivates the reactivity of the carboxylic acid.
Our retrosynthetic route of CDA3a was devised as a
convergent synthesis of linking the cyclic peptide core and the
acyl chain via a chemoselective Ser ligation30−32 (Figure 2),
To overcome the above obstacle, we adjusted the sequence
of formation of esterification and amidation. As shown in
Scheme 2, the protection of the primary amino group of 12
Figure 2. Retrosynthetic analysis of CDA3a.
Scheme 2. Synthesis of Tripeptide 4
which would generate CDA3a and further derivatives with
variation of the fatty acyl substituent from a common
precursor. The acid labile trans-2,3-epoxyhexanoyl tail cannot
tolerate the last step global deprotection condition (95% TFA/
5% H2O) with the conventional strategy using the side-chain
protected peptide precursor, thus another rationality for our
Ser ligation-based synthetic route is to avoid using strong
acidic conditions with the trans-2,3-epoxyhexanoyl group being
present. The macrocyclization site is selected between 3-
HOAsn and achiral amino acid glycine to avoid the
epimerization issue during the cyclization. Another foreseen
challenge lies in the esterification between Z-dehydrotypto-
phan and threonine, as the reactivity of Z-dehydrotyptophan is
not fully documented in the literature.
The synthesis of the requisite 3-HOAsn 3 has been reported
in our previous synthesis of A54145.33 Foreseeing the
challenge of on-resin esterification between Z-dehydrotypto-
phan and threonine, we planned to construct a Z-
dehydrotyptophan-containing tripeptide building block 4 via
solution phase reactions, which is suitable for Fmoc-SPPS
(solid phase peptide synthesis). As shown in Scheme 1, a direct
dehydrogenation precursor 6 was first prepared through
coupling, deprotection, and coupling with the commercially
available compound 5. Then the direct dehydrogenation34,35 of
the tripeptide 6 was screened with a variety of oxidants such as
DDQ, CAN, and PhNO/ZrCl4; none of which were successful.
Therefore, we modified the synthetic sequence and conducted
the direct dehydrogenation on the Trp residue first. According
with phthalic acid was followed by coupling with Alloc-L-Thr-
OMe to give 13 in a moderate yield. Then a direct
dehydrogenation of 13 was conducted to provide the
corresponding depsidipeptide 14 in 85% yield as a single Z-
isomer. Sequential treatment of 14 with ethylenediamine to
release the free amine followed by amidation by being treated
with freshly prepared symmetric anhydride of Fmoc-Glu-
(OtBu)-OH afforded 7 in 33% yield over 2 steps. Selective
hydrolysis of the methyl ester of 7 could be achieved by being
treated with Me3SnOH36 to give the desired tripeptide 4 in
86% yield. Collectively, our results showed that dehydro-
tryptophan has the deactivated carboxylic acid group but
maintains the amino reactivity toward acylation.
Next, the synthesis of epoxyhexanoyl salicylic aldehyde ester
was based on the Sharpless asymmetric epoxidation.37 As
depicted in Scheme 3, asymmetric epoxidation of the known
allylic alcohol 15 provided epoxide 16. Treatment of 2S,3S-16
B
https://dx.doi.org/10.1021/acs.orglett.0c01544
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
were tested (see Table S1). COMU in combination with 2,6-
lutidine proved to the best condition for coupling D-Hpg as
shown in Scheme 4. Then the resultant resin-linked peptide
was subsequently coupled with Fmoc-L-Asp-OH, Fmoc-D-Trp-
OH, and Z-dehydrotyptophan-containing tripeptide 4 to afford
19. In order to avoid facile 2,5-diketopiperazine formation, the
deprotection of the Fmoc group used 20% piperidine in DMF
for 1 min to release free amine, which immediately underwent
amidation with 3-HOAsn 3. Then deprotection of TBS and the
Alloc group released the free amino group. It was noted that in
order to avoid an intramolecular O-to-N acyl shift, the time of
the deAlloc step could not be more than 1 h. The resulting free
amino group was coupled with Boc-L-Ser(OtBu)-OH under
standard conditions to afford the desired linear peptide chain
20. After deprotecting the N-terminal Fmoc group of the linear
peptide, the side chain protected linear peptide was released
from the trityl resin with AcOH/TFE/CH2Cl2 to give rise to
the acyclic precursor. The macrocyclization proceeded
Scheme 3. Synthesis of Epoxyhexanoyl Salicylic Aldehyde
Ester 2
with ruthenium chloride and sodium periodate produced
carboxylic acid in nearly quantitative yield. The optically active
key carboxylic acid was coupled with salicylaldehyde in the
presence of DIC to afford the epoxyhexanoyl salicylaldehyde
ester 2 in 82% yield over two steps.
With all building blocks in hand, we continued with the total
synthesis of CDA3a. According to the retrosynthesis analysis,
the Fmoc-Gly-OH was incorporated into a 2-chlorotrityl
chloride resin to start Fmoc-SPPS. Due to the high proneness
to epimerization of the D-Hpg during SPPS,38−40 different
conditions for Fmoc-removal and different coupling reagents
Scheme 4. Synthesis of Syntheses of CDA3a
C
https://dx.doi.org/10.1021/acs.orglett.0c01544
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
smoothly in CH2Cl2 with PyBOP/HOAt/DIEA as the
coupling reagent to afford the cyclic peptide. Then the global
deprotection of the side chain protective group gave rise to the
desired cyclic core 21. It is worth noting that if the cocktail was
changed to TFA/TIPS/H2O (95/2.5/2.5, v/v/v), the double
bond in Z-dehydrotryptophan was reduced.
Table 1. Minimal Inhibitory Concentrations (in μg/mL) of
CDA3a and Its Analogues
bacterial
strain
MRSA
SA1114
SA
Streptococcus
faecalis SF
Enterococcus
ATCCET
ATCC29213
a
1
512
>32
256
>32
256
>32
>32
4
>32
8
16
4
>32
>1024
b
b
b
b
25−31
32
33
34
35
36
37
38
39
>32
>32
With the cyclic core 21 in hand, serine ligation was then
used to complete the total synthesis of CDA3a as shown in
Scheme 4. The ligation proceeded efficiently to couple 21 and
2 in pyridine/AcOH (1:1, mol:mol) with a complete
conversion to afford the intermediate 22 in 6 h, and then
the N,O-benzylidene acetal intermediate was treated with
TFA/AcOH/H2O (1:4:4, v/v/v) for 3 h to give the desired
CDA3a 1 in 9.3% yield based on the 100 mg resin (0.05 mmol
loading), after reversed-phase HPLC purification. It is worth
mentioning that the acid hydrolysis of the N,O-benzylidene
acetal intermediate with a low percent of TFA was
accomplished cleanly without any epoxy ring opening product
detected. The 1H NMR data for synthetic CDA3a agreed with
the reported one19 for the natural product (see Figure S129).
As a comparison, the epoxyhexanoyl pentafluorophenol ester
failed to couple with CDA3a core 21 (Figure S2), which
demonstrated the effectiveness and uniqueness of late-stage
serine ligation for CDA3a synthesis.
To explore the significance of the acyl tail on its antibacterial
activity, we also designed and synthesized a library of CDA3a
analogues containing different lengths, different α,β-substitu-
tions, or different terminal substitutions of acyl tails41 (see the
SI for synthetic details). Saturated acyl acids with different
lengths (C10, C12, C14, C16) were coupled with salicylic
aldehyde, followed by a subsequent serine ligation with cyclic
core 21 giving 25−29 in 37%−57% yield (Scheme 5). The
b
b
8
8
4
4
4
8
>32
8
2
4
4
2
4
4
8
>32
2
2
4
>32
b
b
8
16
4
>32
b
b
b
b
b
b
>32
2
>32
40
2
a
b
The highest concentration tested was 1024 μg/mL. The highest
concentration tested was 32 μg/mL.
whose side chain lengths were more than 10 carbons and
saturated lipid acids, did not show any antibacterial properties
as 31, whose side chain lengths were less than 10 carbons and
had an α,β-double bond, while the synthetic analogues 32−37,
39, and 40, whose side chain lengths were equal to or more
than 10 carbons and had an α,β-double bond or α,β-epoxy
group, showed much improved antibacterial activity. Surpris-
ingly, although the synthetic analogues 33, 35, 37, and 40
containing an even number of carbons showed comparable
antibacterial activity to Streptococcus faecalis SF and Enter-
ococcus ET6, synthetic analogues 34 and 36 containing an odd
number of carbons did not show any antibacterial activity to
them. Unexpectedly, synthetic analogues 30 and 38, which
contain a terminal alkyne in the side chain, lost all the
antibiotic activity. Therefore, the MIC result indicated that the
side chain, including length, substituent at the α,β-position,
and the terminal position, seemed to be important for potent
antibacterial activity.
Scheme 5. Synthesis of CDA3a Derivatives with Different
Acyl Acid Tails
In summary, we have developed a convergent synthetic
route for the total synthesis of the CDA3a via late-stage serine
ligation, which was also used to prepare a small library of
CDA3a analogues to establish a preliminary structure−activity
relationship (SAR). The key features of the synthesis include a
solution for the preparation of dehydrotryptophan-containing
depsipeptides and a late-stage serine ligation. Several analogues
with greatly enhanced antibacterial activity were identified, in
particular with compound 40 being the most potent analogue
with 256−512-fold greater potency against VRE and MRSA
than the parent CDA3a. Our SAR studies showed that the
length, α,β-substitution, and terminal substitution of a fatty
acid tail are important for its bioactivity. We anticipate that the
findings in this study will generate a new understanding of
calcium dependent cyclic peptide antibiotics and provide a
roadmap for further development.
α,β-unsaturated analogues 30−37 with different lengths (C8,
C10, C12, C13, C14, C15, C16) or terminal-alkyne were prepared
under identical conditions in 38%−52% yield. The α,β-epoxy
analogues 38−40 with different lengths (C10, C14) or terminal-
alkyne were also prepared expecting to be compared with the
α,β-unsaturated analogues. After purification by reversed-phase
HPLC, the α,β-epoxy analogues were isolated in 35%−43%
yield over 2 steps
The synthetic CDA3a and all above-mentioned analogues
were subjected to the assessment of their antibacterial activities
by determining their minimal inhibitory concentration (MIC)
on various Gram-positive bacteria strains including methicillin-
susceptible S. aureus strain ATCC29213 and methicillin-
resistant S. aureus clinical isolates. As shown in Table 1,
synthetic CDA3a displayed poor anti-SA and anti-MRSA
activity, similarly as reported.9 Synthetic analogues 25−29,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01544.
■
sı
Experimental procedures, characterization data of
synthetic compounds, and 1D and 2D NMR spectra
(PDF)
D
https://dx.doi.org/10.1021/acs.orglett.0c01544
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(12) Wu, C.; Shang, Z.; Lemetre, C.; Ternei, M. A.; Brady, S. F. J. J.
Am. Chem. Soc. 2019, 141, 3910−3919.
AUTHOR INFORMATION
Corresponding Author
■
(13) Strieker, M.; Marahiel, M. A. ChemBioChem 2009, 10, 607−
616.
Xuechen Li − Department of Chemistry, State Key Laboratory of
Synthetic Chemistry, The University of Hong Kong, Hong Kong,
P. R. China; orcid.org/0000-0001-5465-7727;
Email: xuechenl@hku.hk
(14) Wood, T. M.; Martin, N. I. MedChemComm 2019, 10, 634−
646.
(15) Lakey, J. H.; Lea, E. J. A.; Rudd, B. A. M.; Wright, H. M.;
Hopwood, D. A. A. Microbiology 1983, 129, 3565−3573.
(16) Kempter, C.; Kaiser, D.; Haag, S.; Nicholson, G.; Gnau, V.;
Authors
̈
Walk, T.; Gierling, K. H.; Decker, H.; Zahner, H.; Jung, G.; Metzger,
Delin Chen − Department of Chemistry, State Key Laboratory
of Synthetic Chemistry, The University of Hong Kong, Hong
Kong, P. R. China
Kathy Hiu Laam Po − Department of Infectious Diseases Public
Health, Jockey Club College of Veterinary Medicine and Life
Sciences, The City University of Hong Kong, Kowloon, Kowloon,
Hong Kong, P. R. China
Pilar Blasco − Department of Chemistry, State Key Laboratory
of Synthetic Chemistry, The University of Hong Kong, Hong
Kong, P. R. China
Sheng Chen − Department of Infectious Diseases Public Health,
Jockey Club College of Veterinary Medicine and Life Sciences,
The City University of Hong Kong, Kowloon, Kowloon, Hong
Kong, P. R. China; orcid.org/0000-0003-3526-7808
J. W. Angew. Chem., Int. Ed. Engl. 1997, 36, 498−501.
(17) Hojati, Z.; Milne, C.; Harvey, B.; Gordon, L.; Borg, M.; Flett,
F.; Wilkinson, B.; Sidebottom, P. J.; Rudd, B. A. M.; Hayes, M. A.;
Smith, C. P.; Micklefield, J. Chem. Biol. 2002, 9, 1175−1187.
(18) Milne, C.; Powell, A.; Jim, J.; Nakeeb, M. A.; Smith, C. P.;
Micklefield, J. J. Am. Chem. Soc. 2006, 128, 11250−11259.
(19) Mahlert, C.; Kopp, F.; Thirlway, J.; Micklefield, J.; Marahiel, M.
A. J. Am. Chem. Soc. 2007, 129, 12011−12018.
(20) Powell, A.; Nakeeb, M. A.; Wikinson, B.; Micklefield, J. Chem.
Commun. 2007, 26, 2683−2685.
(21) Neary, J. M.; Powell, A.; Gordon, L.; Milne, C.; Flett, F.;
Wilkinson, B.; Smith, C. P.; Micklefield, J. Microbiology 2007, 153,
768−776.
(22) Amir-Heidari, B.; Thirlway, J.; Micklefield, J. Org. Lett. 2007, 9,
1513−1516.
(23) Amir-Heidari, B.; Micklefield, J. J. Org. Chem. 2007, 72, 8950−
8953.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01544
(24) Amir-Heidari, B.; Thirway, J.; Micklefield, J. Org. Biomol. Chem.
2008, 6, 975−978.
Notes
(25) Powell, A.; Borg, M.; Amir-Heidari, B.; Neary, J. M.; Thirlway,
J.; Wilkinson, B.; Smith, C. P.; Micklefield, J. J. Am. Chem. Soc. 2007,
129, 15182−15191.
The authors declare no competing financial interest.
̈
(26) Kopp, F.; Linne, U.; Oberthur, M.; Marahiel, M. A. J. Am.
Chem. Soc. 2008, 130, 2656−2666.
ACKNOWLEDGMENTS
■
This work was supported by the Research Grants Council-
Collaborative Research Fund of Hong Kong (C7038-15G,
C5026-16G), the Area of Excellence Scheme of the University
Grants Committee of Hong Kong (AoE/P-705/16), and the
Croucher Foundation.
(27) Uguru, G. C.; Milne, C.; Borg, M.; Flett, F.; Smith, C. P.;
Micklefield, J. J. Am. Chem. Soc. 2004, 126, 5032−5033.
(28) Jiang, J.; Ma, Z.; Castle, S. L. Tetrahedron 2015, 71, 5431−
5451.
(29) Kaur, H.; Heapy, A. M.; Brimble, M. A. Org. Biomol. Chem.
2011, 9, 5897−5907.
(30) Liu, H.; Li, X. Acc. Chem. Res. 2018, 51, 1643−1655.
(31) Chow, H. Y.; Zhang, Y.; Matheson, E.; Li, X. Chem. Rev. 2019,
119, 9971−10001.
REFERENCES
■
(1) Blair, J. M.; Webber, M. A. J.; Baylay, A. J.; Ogbolu, D. O.;
Piddock, L. J. V. Nat. Rev. Microbiol. 2015, 13, 42−51.
(2) Abdalla, M. A.; McGaw, L. J. Molecules 2018, 23, 2080−2098.
(3) Ling, L. L.; Schneider, T.; Peoples, A. J.; Spoering, A. L.; Engels,
(32) Li, X.; Lam, H. Y.; Zhang, Y.; Chan, C. K. Org. Lett. 2010, 12,
1724−1727.
(33) Chen, D.; Chow, H. Y.; Po, K. H. L.; Ma, W.; Leung, E. L. Y.;
Sun, Z.; Liu, M.; Chen, S.; Li, X. Org. Lett. 2019, 21, 5639−5644.
(34) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero,
C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678−8693.
(35) Dai, Q.; Xie, X.; Xu, S.; Ma, D.; Tang, S.; She, X. Org. Lett.
2011, 13, 2302−2305.
̈
I.; Conlon, B. P.; Mueller, A.; Schaberle, T. F.; Hughes, D. E.; Epstein,
S.; Jones, M.; Lazarides, L.; Steadman, V. A.; Cohen, D. R.; Felix, C.
R.; Fetterman, K. A.; Millett, W. P.; Nitti, A. G.; Zullo, A. M.; Chen,
C.; Lewis, K. Nature 2015, 517, 455−459.
(4) Hover, B. M.; Kim, S. H.; Katz, M.; Charlop-Powers, Z.; Owen,
J. G.; Ternei, M. A.; Maniko, J. M.; Estrela, A. B.; Molina, H.; Park, S.;
Perlin, D. S.; Brady, S. F. Nat. Microbiol. 2018, 3, 415−422.
(5) Wu, C.; Shang, Z.; Lemetre, C.; Ternei, M. A.; Brady, S. F. J. Am.
Chem. Soc. 2019, 141, 3910−3919.
(36) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S.
Angew. Chem., Int. Ed. 2005, 44, 1378−1382.
(37) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S.
Y.; Sharpless, B. J. Am. Chem. Soc. 1987, 109, 5765−5780.
(38) Elsawy, M. A.; Hewage, C.; Walker, B. J. Pept. Sci. 2012, 18,
302−311.
(39) Brieke, C.; Cryle, M. J. Org. Lett. 2014, 16, 2454−2457.
(40) Liang, C.; Behnam, M. A. M.; Sundermann, T. R.; Klein, C. D.
Tetrahedron Lett. 2017, 58, 2325−2329.
(41) Corcilius, L.; Liu, D. Y.; Ochoa, J. L.; Linington, R. G.; Payne,
R. J. Org. Biomol. Chem. 2018, 16, 5310−5320.
(6) Sousa, M. C. Nature 2019, 576, 389−390.
(7) Debono, M.; Barnhart, M.; Carrell, C. B.; Hoffmann, J. A.;
Occolowitz, J. L.; Abbott, B. J.; Fukuda, D. S.; Hamill, R. L.; Biemann,
K.; Herlihy, W. C. J. J. Antibiot. 1987, 40, 761−777.
(8) Silverman, J. A.; Mortin, L. I.; VanPraagh, A. D. G.; Li, T.; Alder,
J. J. Infect. Dis. 2005, 191, 2149−2152.
(9) Boeck, L. D.; Papiska, H. R.; Wetzel, R. W.; Mynderse, J. S.;
Fukuda, D. S.; Mertz, F. P.; Berry, D. M. J. Antibiot. 1990, 43, 587−
593.
(10) Counter, F. T.; Allen, N. E.; Fukuda, D. S.; Hobbs, J. N.; Ott, J.;
Ensminger, P. W.; Mynderse, J. S.; Preston, D. A.; Wu, C. Y. E. J.
Antibiot. 1990, 43, 616−622.
(11) Hover, B. M.; Kim, S. H.; Katz, M.; Charlop-Powers, Z.; Owen,
J. G.; Ternei, M. A.; Maniko, J. M.; Estrela, A. B.; Molina, H.; Park, S.;
Perlin, D. S.; Brady, S. F. Nat. Microbiol. 2018, 3, 415−422.
E
https://dx.doi.org/10.1021/acs.orglett.0c01544
Org. Lett. XXXX, XXX, XXX−XXX