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Minireview: Carbapenems: Past, Present, and Future
Minireview: Carbapenems: Past, Present, and Future
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0066-4804/11/$12.00 doi:10.1128/AAC.00296-11
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
MINIREVIEW
Carbapenems: Past, Present, and Future䌤
Krisztina M. Papp-Wallace,1,2 Andrea Endimiani,1,2,3
Magdalena A. Taracila,2 and Robert A. Bonomo1,2,4,5*
Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland,
Ohio 441061; Institute for Infectious Diseases, University of Bern 3010, Bern, Switzerland3;
and Departments of Medicine,2 Pharmacology,4 and Molecular Biology and Microbiology,5
In this review, we summarize the current “state of the art” of carbapenem antibiotics and their role in our
antimicrobial armamentarium. Among the -lactams currently available, carbapenems are unique because
they are relatively resistant to hydrolysis by most -lactamases, in some cases act as “slow substrates” or
inhibitors of -lactamases, and still target penicillin binding proteins. This “value-added feature” of inhibiting
-lactamases serves as a major rationale for expansion of this class of -lactams. We describe the initial
discovery and development of the carbapenem family of -lactams. Of the early carbapenems evaluated,
thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent
carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those
of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are
presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and
biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development
of these versatile and potent compounds, as they have served us well for more than 3 decades.
Carbapenems play a critically important role in our antibi- Gram-positive bacterium Streptomyces clavuligerus. Olivanic
otic armamentarium. Of the many hundreds of different -lac- acids possess a “carbapenem backbone” (a carbon at the 1
tams, carbapenems possess the broadest spectrum of activity position, substituents at C-2, a C-6 ethoxy, and sp2-hybridized
and greatest potency against Gram-positive and Gram-nega- C-3) and act as broad-spectrum -lactams (25, 27, 199). Due to
tive bacteria. As a result, they are often used as “last-line chemical instability and poor penetration into the bacterial
agents” or “antibiotics of last resort” when patients with infec- cell, the olivanic acids were not further pursued (192). Shortly
tions become gravely ill or are suspected of harboring resistant thereafter, two superior -lactamase inhibitors were discov-
bacteria (23, 174–176, 229). Unfortunately, the recent emer- ered: (i) clavulanic acid (compound 2) from S. clavuligerus, the
gence of multidrug-resistant (MDR) pathogens seriously first clinically available -lactamase inhibitor (25), and (ii)
threatens this class of lifesaving drugs (189). Several recent thienamycin (compound 3) from Streptomyces cattleya (Fig.
studies clearly show that resistance to carbapenems is increas- 1A) (3, 112). Thienamycin was the first “carbapenem” and
ing throughout the world (35, 64, 73, 123, 151, 155, 173, 200). would eventually serve as the parent or model compound for
Despite this menacing trend, our understanding of how to best all carbapenems. A series of other carbapenems were also
use these agents is undergoing a renaissance, especially con- identified (30, 92, 107, 147, 149, 162, 163, 172, 233); however,
cerning their role with regard to -lactamase inhibition. In this the discovery of thienamycin was paramount.
context, we view the number, type, and diversity of carbapen- The term “carbapenem” is defined as the 4:5 fused ring
ems as compelling reasons to explore these compounds for new lactam of penicillins with a double bond between C-2 and C-3
insights into drug development. but with the substitution of carbon for sulfur at C-1. The
hydroxyethyl side chain of thienamycin is a radical departure
IN THE BEGINNING… from the structure of conventional penicillins and cephalo-
sporins, all of which have an acylamino substituent on the
In the late 1960s, as bacterial -lactamases emerged and
-lactam ring; the stereochemistry of this hydroxyethyl side
threatened the use of penicillin, the search for -lactamase
chain is a key attribute of carbapenems and is important for
inhibitors began in earnest (38, 199). By 1976, the first -lac-
activity (95). Remarkably, thienamycin demonstrated potent
tamase inhibitors were discovered; these olivanic acids (com-
broad-spectrum antibacterial and -lactamase inhibitory ac-
pound 1 in Fig. 1) were natural products produced by the
tivity (112, 113). This notable discovery was first reported at
the 16th Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC) meeting in 1976 (3, 112). Al-
* Corresponding author. Mailing address: Infectious Diseases Section, though thienamycin is a “natural product” and the biosyn-
Louis Stokes Cleveland Department of Veterans Affairs Medical Center,
10701 East Blvd., Cleveland, OH 44106. Phone: (216) 791-3800, ext. 4801.
thetic pathway was determined (160), yields from the
Fax: (216) 231-3482. E-mail: robert.bonomo@med.va.gov. purification process were low. With time, the synthetic prep-
䌤
Published ahead of print on 22 August 2011. aration of thienamycin assumed greater importance, espe-
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4944 MINIREVIEW ANTIMICROB. AGENTS CHEMOTHER.
available carbapenems are R at C-8 and trans about the about the C-5OC-6 bond, and has a methyl at C-1 and a
C-5OC-6 bond. Carbapenems with a pyrrolidine moiety (pa- hydroxyethyl at C-6, most modifications are at the R1 side
nipenem, meropenem, ertapenem, and doripenem) among chain (at position C-2). Thus, carbapenems are unique com-
various cyclic amines as a side chain have a broader antimi- pared to other -lactams, which tend differ in both R1 and R2
crobial spectrum (219). side chains. The reader is referred to R. B. Woodward’s clas-
Synthesis. As mentioned above, several chemical ap- sical discourse on this matter (249).
proaches were developed for the synthesis of carbapenems Mechanism of action. As a class of -lactams, carbapenems
since fermentation was not an efficient method for production are not easily diffusible through the bacterial cell wall (131).
(9, 28, 86, 142, 183, 201). Natural products (L-Cys, L-Val, L-␣- Generally speaking, carbapenems enter Gram-negative bacte-
amino adipic acid, and S-adenosyl-Met) were often used as ria through outer membrane proteins (OMPs), also known as
starting material for production of carbapenems, and the syn- porins. After transversing the periplasmic space, carbapenems
thetic approach was largely influenced by the desired stereo- “permanently” acylate the PBPs (for the mechanism, see Fig.
chemistry of the final compound. In addition, once a carbap- 3A) (81, 228). PBPs are enzymes (i.e., transglycolases, trans-
enem is developed which has an R configuration at C-8, is trans peptidases, and carboxypeptidases) that catalyze the formation
4946 MINIREVIEW ANTIMICROB. AGENTS CHEMOTHER.
production of a new carbapenem-resistant PBP (100, 109, 134). tance mechanisms (e.g., porin loss) (65, 116, 126, 128, 197,
Expression of -lactamases and efflux pumps, as well as porin 217).
loss and alterations in PBP, are all associated with carbapenem Structure-function: considerations among carbapenemases.
resistance in Gram-negative rods (155, 178, 245). The mecha- Several class A carbapenemase -lactamases (i.e., KPC-2,
nism that has been investigated in the most detail is the pro- SME-1, and NmcA) have been crystallized (103, 182, 214, 222).
duction of -lactamases, and thus it is discussed in greater These enzymes possess a distinctive set of active-site residues
detail here than the other mechanisms of resistance. that are suspected to be involved in the hydrolysis of carbap-
-Lactamases. -Lactamases are a major antibiotic resis- enems. We will review here their important features.
tance mechanism employed by bacteria; these periplasmic en- A unique attribute of class A carbapenemases (i.e., KPC,
zymes hydrolyze -lactam antibiotics, preventing the drug from SME, and NmcA) is the presence of a disulfide bond between
reaching the PBP target. Presently, -lactamases are classified Cys69 and Cys238 (Ambler numbering system [4]); this bond
into four distinct classes based on structural similarities changes the overall shape of the active site by altering the
(classes A, B, C, and D) or four groups based on hydrolytic and distance between active-site residues. The distance between
inhibitor profiles (1 to 4) (4, 26). Class B -lactamases use Ser70 and Thr237 is less, the length of the active site is de-
Zn2⫹ to inactivate -lactams, and all are carbapenemases. creased as indicated by the distance between Glu166 and
Class A, C, and D -lactamases use a serine as a nucleophile to Thr237, and the space between Asn132 and Asn170 is in-
hydrolyze the -lactam bond. creased in comparison to SHV-1 and TEM-1. In addition,
Carbapenemases are specific -lactamases with the ability to several active-site residues have different amino acids in com-
hydrolyze carbapenems. Production of -lactamases appears parison to SHV-1 and TEM-1 (e.g., Thr/Ser237, His/Trp105,
to be the most widespread cause of carbapenem resistance, Arg220, and Glu276). These significant structural changes de-
since the documentation of their distribution in different bac- crease the steric hindrance caused by the C-6 hydroxyethyl side
terial species is extensive (189, 242, 243). An increasing num- chain of carbapenems, which is a key determinant in inhibition
ber of class A carbapenemases (e.g., KPC and GES enzymes), of noncarbapenemase class A -lactamases and allows class A
class B metallo--lactamases (e.g., VIM, IMP, and NDM carbapenemases to hydrolyze imipenem with kcat values (turn-
-lactamases), and class D carbapenemases (e.g., OXA-23, over rates) from 10 to 1,000 s⫺1. Mutagenesis studies of the
⫺24/40, ⫺48, ⫺51, ⫺55, ⫺58, and ⫺143) have recently SME-1 and KPC-2 -lactamases have revealed several sites
emerged (187, 189, 242, 243, 253). In addition, overproduction that may be necessary for carbapenem resistance (127, 170,
of class C -lactamases, such as CMY-10 and PDC -lactama- 171). However, the finding of a single residue responsible for
ses, which are not robust carbapenemases, can lead to carbap- carbapenem resistance remains elusive.
enem resistance, especially when combined with other resis- GES-2 is unique to the class A carbapenemase family be-
4948 MINIREVIEW ANTIMICROB. AGENTS CHEMOTHER.
cause a single amino acid substitution (Gly170Asn) changes tamases function as mono-Zn2⫹ enzymes, and binding of an-
GES-1, which is an extended-spectrum -lactamase (ESBL), other Zn2⫹ decreases activity.
into a carbapenemase. GES-2 has a very low kcat for imipenem The CphA -lactamase is a strict carbapenemase of subclass
of ⬃0.01 s⫺1. The Gly170Asn substitution is found in the ⍀ B2. CphA has been crystallized with one Zn2⫹ ion, two Zn2⫹
loop of GES-2. Molecular modeling studies with imipenem ions, and a biapenem intermediate trapped in the active site
and the in silico-generated GES-2 suggest that the shape of the (15, 16, 40, 67, 208, 209, 250–252). Previously, the second
active site accommodates the hydroxyethyl moiety (211). In inhibitory Zn2⫹ binding site was postulated to be remote from
addition, Asn170 interacts with the predicted hydrolytic water the active site (40, 42). However, the dizinc crystal structure of
molecule. Another mutation at Gly170 to Ser (mimicking CphA reveals that this Zn2⫹ sits in the second Zn2⫹ binding
GES-5) results in increased carbapenemase activity in compar- site, similar to the case with subclass B1 and B3 metallo--
ison to that of GES-2; GES-5 exhibits a kcat for imipenem of lactamases (21, 22, 47, 77, 253, 254). Quantum mechanics and
0.5 s⫺1 (61). Initial molecular modeling studies suggest that molecular mechanics have been used to dissect the mechanism
imipenem is bound in a similar manner in GES-5 and GES-1, of carbapenem turnover by CphA. A mechanism is presented
not explaining the increase in kcat (211). Examining the micro- in Fig. 5A and is predicted to occur in a single step (67, 208,
scopic rate constants for imipenem with GES-1, -2, and -5 250). In this mechanism, His118 is the general base that coor-
reveals that the rate-limiting step for GES-1 and GES-2 is dinates a water molecule with Asp120; this water serves as the
acylation (61). The rate of acylation for imipenem is enhanced nucleophile for -lactam bond cleavage. Asp120, Cys221, and
by 5,000-fold for GES-5 and is no longer rate limiting. Deacy- His263 coordinate Zn2⫹ along with a water molecule, which
lation is also enhanced in GES-5 but becomes the rate-limiting also hydrogen bonds to the carboxylate of carbapenems. This
step in imipenem hydrolysis. Further molecular modeling stud- second water molecule donates a proton to -lactam nitrogen
ies with GES -lactamases have disclosed the importance of to complete the hydrolysis event. Zn2⫹ anchors the critical
the movement of Trp105 to the interior of the active site, which deacylation water molecule and stabilizes the complex.
may alter the acylation rates (111). In contrast, with subclass B1 and B3 di-Zn2⫹ metallo--
Class B -lactamases require one or two Zn2⫹ cations for lactamases, one Zn2⫹ atom decreases the pKa of the water
activity and are subdivided into three groups, B1, B2, and B3, molecule to generate a hydroxyl nucleophile for the attack of
based on sequence alignments and structural analysis (14). All the -lactam, while the other Zn2⫹ stabilizes the tetrahedral
three groups hydrolyze carbapenems (kcat for imipenem of 2 to intermediate (Fig. 5B) (14). A recent study reveals a common
1,000 s⫺1), but -lactamases in group B2 are strictly carbap- catalytic feature of mono-Zn2⫹ and di-Zn2⫹ metallo--lacta-
enemases. B1 and B3 enzymes typically exhibit maximum mases using GOB-18, a member of the B3 metallo--lactama-
activity when bound by two Zn2⫹ ions. Conversely, B2 -lac- ses (122). This enzyme is fully active with only one Zn2⫹
Downloaded from http://aac.asm.org/ on December 31, 2018 by guest
FIG. 5. (A) Mechanism of carbapenem hydrolysis by CphA. (B) Subclass B1 and B3 metallo--lactamase active sites. (C) Stabilization of the
anionic intermediate in GOB-18.
4949
4950 MINIREVIEW ANTIMICROB. AGENTS CHEMOTHER.
bound. Studies to date indicate that only one Zn2⫹ is essential zyme form of OXA-24/40 is largely unchanged by the binding
for GOB-18 and its role is to anchor the substrate and stabilize of doripenem. The presence of this bridge causes the pyrroli-
the anionic intermediate and not for nucleophile activation dine/sulfonamide group to bind in a conformation different
(Fig. 5C) (59). A critical feature of the mono-Zn2⫹ mechanism from that of doripenem bound to OXA-1. This change in
in GOB-18 is the positioning of the Zn2⫹ atom in the active conformation is due to the different tautomeric state of dorip-
site. enem in the active site and may correlate with why carbapen-
Class C -lactamases are not generally classified as carbap- ems are turned over by OXA-24/40 but not OXA-1.
enemases. Most enzymes in this class have weak activity toward Carbapenems and inhibition of -lactamases. Carbapenems
carbapenems (kcat ⬍ 4 s⫺1) if any activity at all (128). So when can behave as “slow substrates” or inhibitors of noncarbapen-
an AmpC enzyme is found in a strain with other resistance emase (serine) -lactamases (18, 29, 44, 145). This fortuitous
mechanisms, resistance toward carbapenems may be enhanced observation serves as a major point of interest in these com-
(129). Curiously, rare class C enzymes that can confer resis- pounds and adds to their “dual function” (i.e., inhibits PBPs
tance to imipenem are described (106, 187, 196, 197). The and -lactamases). Many class A -lactamases are susceptible
that of the intact carbapenem is noted (48). The “fragmented” different carbapenems are now known; these structures com-
carbapenem may also be hydrolyzed. The loss of a hydroxy- plement the above studies and significantly enhance our un-
ethyl group may be a very minor reaction, since crystallo- derstanding of inhibition by carbapenems.
graphic studies of -lactamases with carbapenems do not seem The first crystal structure of a carbapenem with a -lacta-
to support this observation. mases was TEM-1 with imipenem (Fig. 7A) (135). TEM-1
Several crystal structures of -lactamases complexed with complexed with imipenem (1BT5) revealed that the electro-
FIG. 7. (A) TEM-1 and imipenem (PDB identifier 1BT5). (B) TEM-1 Asn132Ala and imipenem (PDB identifier 1JVJ).
4952 MINIREVIEW ANTIMICROB. AGENTS CHEMOTHER.
static and steric hindrance caused by the bulky hydroxyethyl R2 dicted deacylation water molecule is positioned between Ser64
side chain of imipenem at C-6 and Asn132 is one of the main and N4 of imipenem (13).
driving forces behind the slow deacylation and inhibition of Subsequent studies were performed to investigate whether
TEM-1 (135). This subsequent observation was confirmed in a SHV-1, a -lactamase with only 67% amino acid sequence
another atomic structure of TEM-1, where the replacement of similarity with TEM-1, was inactivated in the same manner as
Asn132 with Ala (N132A) resulted in “space” for the hydroxyl- TEM-1. Surprisingly, in the SHV-1 and meropenem crystal
ethyl (Fig. 7B) (244). In the TEM-1 imipenem complex ana- structure, two conformers for meropenem exist: the -lactam
lyzed by Maveyraud et al., the deacylation water molecule carbonyl rests both inside and outside the electrophilic center
forms a hydrogen bond with the hydroxyethyl side chain at C-6, in the complex (159). The two conformers may coincide with
decreasing its nucleophilicity (135). Furthermore, the -lactam the suspected presence of the two tautomers found during
carbonyl of imipenem is observed outside the electrophilic carbapenem hydrolysis; however, the double bond was not
center (i.e., “oxyanion hole”), which is made up of the back- resolved in either structure (224, 254). In both SHV-1 mero-
bone amides of Ser70 and Ala237 in TEM-1. This was not penem complexes, the deacylation water interacts with the
predicted by earlier molecular modeling studies and was an hydroxyethyl group of meropenem, and Glu166 is predicted to
unexpected observation since the ⌬2 isoform of imipenem is be protonated; these occurrences are anticipated to contribute
predicted to be turned over rapidly (244). In the TEM-1 to prolonged deacylation. At about the same time, Kalp and
Asn132-imipenem complex, the carbonyl is located in the oxy- Carey observed the inactivation of SHV-1 with meropenem,
anion hole (244). In both structures, a water molecule is posi- ertapenem, and imipenem using Raman spectroscopy and
tioned between Arg244 and the C-3 carboxylate; this water is identified ”long-lived“ ⌬1 and”short-lived“ ⌬2 isoforms (97).
postulated by Zafarella and Mobashery to play a key role in The M. tuberculosis BlaC class A -lactamase was crystal-
⌬2 3 ⌬1 tautomerization (254). Molecular dynamics further lized with meropenem, ertapenem, and doripenem (90, 230).
added to this understanding by suggesting that in the TEM-1 Crystal structures with ertapenem revealed that ertapenem
imipenem acyl enzyme complex, the -lactam carbonyl can isomerizes from a ⌬2-pyrroline to a ⌬1-pyrroline (Fig. 8A and
move from “outside” the electrophilic center to “inside” during B). In the other BlaC structures, meropenem and doripenem
the course of the simulation. The insights from the crystal are in the ⌬1-pyrroline isoform. Interestingly, the -lactam
structure of the E. coli class C -lactamase AmpC and imi- carbonyl is oriented toward the oxyanion hole in all four struc-
penem was very similar to those for TEM-1 with imipenem tures; this orientation is speculated to occur because of a lack
(carbonyl “outside” the oxyanion hole and ⌬2 isoform). How- of an “Arg244 equivalent” in BlaC. Instead, a less-flexible Thr
ever, the tautomeric water molecule is missing, and the pre- holds the tautomerization water molecule with the carboxylate
VOL. 55, 2011 MINIREVIEW 4953
in the preisomerization crystal, and this water molecule is efflux porins resulting in decreased entry of carbapenems into
absent in the postisomerization crystal. After isomerization, the periplasm exists in P. aeruginosa (89), K. pneumoniae (22,
the hydroxylethyl of ertapenem reorients, preventing deacyla- 247), Enterobacter aerogenes (36), E. coli (166), Serratia marc-
tion by disturbing the basicity of an active-site residue (i.e., escens (132), Proteus mirabilis (240), Citrobacter freundii (126),
Glu166) and the activation of the hydrolytic water molecule. A. baumannii (21, 210), Enterobacter cloacae (191), Proteus
Noncarbapenemase class D -lactamases have been crystal- rettgeri (191), Shigella dysenteriae (69), and Salmonella enterica
lized with carbapenems. These achievements are notable be- (5). Here we briefly describe resistance to clinically available
cause class D -lactamases are usually resistant to inhibitors. carbapenems due to alterations in OprD of P. aeruginosa (77).
The two structures for these distinct enzymes (OXA-13 and The physiological role of OprD is the transport of basic
OXA-1) reveal different findings. In both structures, the car- amino acids (i.e., amino acids with pKas in the range of 9)
bonyl of the carbapenem is inside the oxyanion hole. In the (227). OprD is the main porin used by carbapenems for diffu-
crystal structure of OXA-13 (a close variant of OXA-10) and sion into P. aeruginosa (63, 231). OprD is part of a larger family
meropenem, the water molecule necessary for deacylation is of 19 other porins in P. aeruginosa with 46 to 57% similarity.
acid substitutions in PBPs or acquisition of a novel PBP can MRSA. Of these compounds, 15i (compound 13) and CP5484
cause carbapenem resistance in Haemophilus influenzae, B. (compound 14) may offer interesting possibilities (Fig. 9),
fragilis, S. aureus, Enterococcus faecium, P. mirabilis, E. coli, while the rest are no longer being studied (33, 94, 120, 144, 145,
Listeria monocytogenes, S. pneumoniae, and P. aeruginosa (6, 162, 206, 215, 236, 254).
17, 31, 56, 100, 109, 134, 150, 158, 165, 184, 185, 218). Oral carbapenems. Oral carbapenems are given as prodrugs
to increase intestinal absorption (63, 101, 126–129, 209, 237,
NOVEL CARBAPENEMS: ANYTHING IN THE PIPELINE? 248, 249). These prodrugs get activated by host enzymes in the
intestinal wall or liver. An advantage for these compounds is
Antipseudomonal and/or anti-MRSA carbapenems. The dis- the ability to treat patients in a nonhospital setting and to avoid
covery of “antipseudomonal” and/or “anti-MRSA” antibiotics
the disadvantages of intravenous (i.v.) administration (i.e., in-
is critical and is a major focus of many contemporary research
ability of patients to self-administer, need for strict asepsis, and
groups. As reviewed herein, resistance in P. aeruginosa to
inconvenience).
-lactams is more complex and involves the production of
Tebipenem-pivoxil (compound 15) is the world’s first oral
-lactamases and poor membrane permeability (e.g., efflux
carbapenem in development in Japan (Fig. 9). Tebipenem-
pumps and porins). MRSA’s resistance to -lactams is mainly due
to the low affinity of MRSA PBP2a for -lactams (33). A signif- pivoxil is active against MDR S. pneumoniae (MIC ⫽ 0.06
icant research effort has been dedicated to using carbapenems to mg/liter) and other Gram-positives, as well as the Enterobac-
target these pathogens (2, 3, 8, 10–12, 71, 78, 79, 92, 93, 106–109, teriaceae (82, 93, 143, 148). Tebipenem-pivoxil’s spectrum does
119, 122, 125, 128, 179, 183, 197, 246). Of these compounds, only not include MRSA and P. aeruginosa. It is absorbed well in the
tomopenem (compound 12) made it to clinical trials (12), but intestine (93), with a half-life of 0.3 to 0.5 h in humans with
development has since been discontinued (Fig. 9) (1). otolaryngological infections (105). Tebipenem is also useful in
Specific anti-MRSA carbapenems. Several carbapenems treating pneumonia in children (115).
were designed to target MRSA while maintaining activity Trinem carbapenems. A new class of -lactams, known as
against most Gram-negatives. The anti-MRSA activity is re- the trinems or tribactams, includes tricyclic -lactams that have
lated to the high affinity of these compounds for PBP2a of a penicillin, cephalosporin, or carbapenem backbone. The
MRSA. The R2 side chains present on these compounds are most successful have been tricyclic -lactams with a carbap-
important affinity determinants for interactions with PBP2a of enem backbone, and these compounds are described below.
VOL. 55, 2011 MINIREVIEW 4955
The first carbapenem trinem to be explored was sanfetrinem tance determinants (e.g., carbapenemases, porins, PBPs, and
(compound 16); it can enter phagocytes and thus has the po- efflux pumps), since overcoming resistance is essential in order
tential to kill intracellular pathogens (Fig. 9) (43). But in 2009, to preserve longevity. Therefore, the modification of carbap-
sanfetrinem-cilexetil development ended after phase II clinical enems so that they are not inactivated by -lactamases is an
trials. important goal. The biggest challenges are the metallo--lac-
A rational drug design approach was used to combine the tamases. However, some progress has been made in identifying
antimicrobial activity of the trinem sanfetrinem with the -lac- potential inhibitors (cephalosporin-derived reverse hydroxam-
tamase inhibitory activity of BRL 42715 (compound 17) ates and oximes, phthalic acid derivatives, mitoxantrone,
(Fig. 9) (39). LK-157 (compound 18) differs from sanfetrinem 4-chloromercuribenzoic acid, sulfonyl-triazole analogs, and
in its BRL-42715-derived ethylidene R1 side chain (Fig. 9) (46, NH-1,2,3-triazole-based compounds) (66, 84, 138, 202, 248).
239). It is speculated that the introduction of an ethylidene Alternative inhibitors can include carbapenems with different
bond at C-6 was designed to stabilize the -lactamase inhibi- stereochemistries. Quantum and molecular mechanics may
tor–-lactamase complex. In addition, the hydrophobic ring at hold the key to identifying a scaffold for competitive inhibitors
5. Armand-Lefevre, L., et al. 2003. Imipenem resistance in Salmonella enterica mase-producing Klebsiella pneumoniae and Escherichia coli. Pharmacother-
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