Angewandte
Communications
Chemie
Natural Products Synthesis
Total Synthesis and Activity of the Metallo-b-lactamase Inhibitor
Aspergillomarasmine A
Kalinka Koteva, Andrew M. King, Alfredo Capretta,* and Gerard D. Wright*
Abstract: Resistance to b-lactam antibiotics is mediated
primarily by enzymes that hydrolytically inactivate the drugs
by one of two mechanisms: serine nucleophilic attack or metal-
dependent activation of a water molecule. Serine b-lactamases
are countered in the clinic by several codrugs that inhibit these
enzymes, thereby rescuing antibiotic action. There are no
equivalent inhibitors of metallo-b-lactamases in clinical use,
but the fungal secondary metabolite aspergillomarasmine A
has recently been identified as a potential candidate for such
a codrug. Herein we report the synthesis of aspergillomar-
asmine A. The synthesis enabled confirmation of the stereo-
chemical configuration of the compound and offers a route for
the synthesis of derivatives in the future.
decades, thus resulting in several generations of drugs with
improved pharmacological profiles and ability to evade
resistance. This strategy, while highly successful, is proving
increasingly challenging to pursue with effectiveness. A
parallel approach has been the coformulation of b-lactam
drugs with inhibitors of b-lactamases. This method has also
proven to be highly effective. The introduction of b-lactamase
inhibitors clavulanic acid, tazobactam, sulbactam, and
recently avibactam[2] in various coformulations with penicil-
lins and cephalosporins has extended the lifetime and clinical
efficacy of several drugs. This approach so far has focused on
the SBLs, which have been the most prominent b-lactamases
in pathogenic bacteria. Over the past several years, however,
MBLs have increased in frequency and concern. MBLs,
unlike most SBLs, can inactivate essentially all penicillins,
cephalosporins, and carbapenems, thereby threatening the
majority of clinically used antibiotics. In particular, the
emergence and widespread global distribution of Gram-
negative pathogens harboring the NDM-1 MBL has proven to
be a grave cause of concern.[3] There is a growing clinical need
for inhibitors of MBLs that can be given as codrugs.
b-Lactam antibiotics are the most widely used group of
antimicrobial drugs in the clinic today. The penicillins,
cephalosporins, carbapenems, and monobactams comprise
a family of bactericidal antibiotics that share the b-lactam ring
that is the reactive moiety of this class of drugs. Resistance to
b-lactams can occur through altered antibiotic uptake or
efflux, or the synthesis of insensitive target proteins (the cell-
wall biosynthetic enzymes that cross-link peptidoglycans), but
it is a large group of hydrolytic enzymes, the b-lactamases,
that represent the principal mode of resistance and drug
failure in the clinic. b-Lactamases are subdivided by their use
of one of two general chemical mechanisms that result in
hydrolytic ring-opening reactions. Serine b-lactamases (SBLs)
use an active-site serine residue in a covalent capture
mechanism that results in the formation of a transient acyl
enzyme intermediate, followed by hydrolytic release of the
inactive product. Metallo-b-lactamases (MBLs) on the other
hand employ active-site metals (one or two Zn2+ centers) to
activate an active-site water molecule that acts as a nucleo-
phile in b-lactam ring opening.[1]
We have recently shown that the fungal natural product
aspergillomarasmine A (AMA, Scheme 1) is a potent inacti-
Scheme 1. Aspergillomarasmine A (AMA) and toxin A.
To overcome the emergence of b-lactamases in patho-
genic bacteria, new derivatives of b-lactam antibiotics have
been regularly introduced to the market over the past
vator of MBLs.[4] AMA operates by a zinc-chelation mech-
anism resulting in an inactive enzyme. NDM and VIM MBLs
are particularly sensitive to the action of AMA. Furthermore,
AMA in combination with meropenem successfully cured
mice infected with a lethal dose of Klebsiella pneumoniae
harboring the NDM-1 MBL, thus demonstrating the potential
of AMA as a candidate MBL inhibitor that could find use as
a codrug with b-lactam antibiotics.
[*] Dr. K. Koteva, A. M. King, Prof. A. Capretta, Prof. G. D. Wright
Michael G. DeGroote Institute for Infectious Disease Research
McMaster University
1280 Main Street West, Hamilton, ON (Canada)
E-mail: capretta@mcmaster.ca
We obtained AMA through fermentation of a producing
strain of Aspergillus versicolor. A study of AMA in the past
revealed a lack of clarity on the absolute configuration of the
natural product. In the original 1965 description of the
discovery of AMA, the stereochemical assignment was l-
aspartic acid, d-aminopropionic acid, and d-aminopropionic
acid (ldd configuration at carbon atoms 3, 6, and 9,
Prof. A. Capretta
Department of Chemistry and Chemical Biology
McMaster University
1280 Main Street West, Hamilton, ON (Canada)
Supporting information and ORCID(s) from the author(s) for this
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 2210 –2212