Unique Side Chain Research Articles

Unique side chain conformation of a leu residue in a triple‐helical structure

Single crystal structures of host-guest peptides, (Pro-Hyp-Gly)(4)-Leu-Hyp-Gly-(Pro-Hyp-Gly)(5) (LOG1) and (Pro-Hyp-Gly)(4)- (Leu-Hyp-Gly)(2)-(Pro-Hyp-Gly)(4) (LOG2), have been determined at 1.6 A and 1.4 A resolution, respectively. In these crystals, the side chain conformations of the Leu residues were (+)gauche-trans. This conformational preference for the Leu side chain in the Leu-Hyp-Gly sequence was explained by stereochemical considerations together with statistical analysis of Protein Data Bank data. In the (+)gauche-trans conformation, the Leu side chain can protrude along the radial direction of the rod-like triple-helical molecule. One strong hydrophobic interaction of the Leu residue was observed between adjacent molecules in the LOG2 crystal. Because the Leu-Hyp-Gly sequence is one of the most frequently occurring triplets in Type I collagen, this strong hydrophobic interaction can be expected in a fibrillar structure of native collagen. All the Leu residues in the asymmetric unit of the LOG1 and LOG2 crystals had water molecules hydrogen bonded to their NH. These water molecules made three additional hydrogen bonds with the Hyp OH, the Gly O[double bond]C, and a water molecule in the second hydration shell, forming a tetrahedral coordination of hydrogen bonds, which allows a smaller mean-square displacement factor of this water oxygen atom than those of other water molecules. These hydrogen bonds stabilize the molecular and packing structures by forming one O[double bond]C(Gly)---W---OH(Hyp) intra-molecular linkage and two NH(Leu)---W---O[double bond]C(Gly) and NH(Leu)---W---OH(Hyp) inter-molecular linkages.

Synthesis and characterization of block copolymers containing poly(di(ethylene glycol) 2-ethylhexyl ether acrylate) by reversible addition–fragmentation chain transfer polymerization

Reversible addition–fragmentation chain transfer (RAFT) polymerization has emerged as one of the important living radical polymerization techniques. Herein, we report the polymerization of di(ethylene glycol) 2-ethylhexyl ether acrylate (DEHEA), a commercially-available monomer consisting of an amphiphilic side chain, via RAFT by using bis(2-propionic acid) trithiocarbonate as the chain transfer agent (CTA) and AIBN as the radical initiator, at 70 °C. The kinetics of DEHEA polymerization was also evaluated. Synthesis of well-defined ABA triblock copolymers consisting of poly(tert-butyl acrylate) (PtBA) or poly(octadecyl acrylate) (PODA) middle blocks were prepared from a PDEHEA macroCTA. By starting from a PtBA macroCTA, a BAB triblock copolymer with PDEHEA as the middle block was also readily prepared. These amphiphilic block copolymers with PDEHEA segments bearing unique amphiphilic side chains could potentially be used as the precursor components for construction of self-assembled nanostructures. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5420–5430, 2007

Synthesis of Psymberic Acid

A short synthesis of the unique side-chain of psymberin (1) - the psymberic acid (4) - is presented. Notable features of it include a highly selective aldol addition and an attempted enzymatic resolution step.

Globally Distributed Mycobacterial Fish Pathogens Produce a Novel Plasmid-Encoded Toxic Macrolide, Mycolactone F

Mycobacterium ulcerans and Mycobacterium marinum are closely related pathogens which share an aquatic environment. The pathogenesis of these organisms in humans is limited by their inability to grow above 35 degrees C. M. marinum causes systemic disease in fish but produces localized skin infections in humans. M. ulcerans causes Buruli ulcer, a severe human skin lesion. At the molecular level, M. ulcerans is distinguished from M. marinum by the presence of a virulence plasmid which encodes a macrolide toxin, mycolactone, as well as by hundreds of insertion sequences, particularly IS2404. There has been a global increase in reports of fish mycobacteriosis. An unusual clade of M. marinum has been reported from fish in the Red and Mediterranean Seas and a new mycobacterial species, Mycobacterium pseudoshottsii, has been cultured from fish in the Chesapeake Bay, United States. We have discovered that both groups of fish pathogens produce a unique mycolactone toxin, mycolactone F. Mycolactone F is the smallest mycolactone (molecular weight, 700) yet identified. The core lactone structure of mycolactone F is identical to that of M. ulcerans mycolactones, but a unique side chain structure is present. Mycolactone F produces apoptosis and necrosis on cultured cells but is less potent than M. ulcerans mycolactones. Both groups of fish pathogens contain IS2404. In contrast to M. ulcerans and conventional M. marinum, mycolactone F-producing mycobacteria are incapable of growth at above 30 degrees C. This fact is likely to limit their virulence for humans. However, such isolates may provide a reservoir for horizontal transfer of the mycolactone plasmid in aquatic environments.

Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH.

Molybdenum cofactor deficiency in humans results in the loss of the activity of molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. The resultant severe phenotype, which includes progressive neurological damage leading in most cases to early childhood death, results primarily from the deficiency of sulfite oxidase. All forms of molybdenum cofactor deficiency are inherited as autosomal recessive traits. The cofactor is an unstable reduced pterin with a unique four-carbon side chain, synthesized by a complex pathway that requires the products of at least four different genes (MOCS1, MOCS2, MOCS3, and GEPH). Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH. MOCS1 and MOCS2 have a bicistronic architecture; i.e., each gene encodes two proteins in different open reading frames. The protein products, MOCS1A and B and MOCS2A and B, are expressed either from different mRNAs generated by alternative splicing or by independent translation of a bicistronic mRNA. The gephyrin protein, encoded by a third locus, is required during cofactor assembly for insertion of molybdenum. A total of 32 different disease-causing mutations, including several common to more than one family, have been identified in molybdenum cofactor-deficient patients and their relatives.

Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor.

We have previously disclosed the first potent and orally effective non-peptide antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475 (1). Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9k: TAK-013). Compound 9k showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC(50)) values of 0.1 and 0.06 nM, respectively. Oral administration of 9k caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, molecular modeling studies indicate that the unique methoxyurea side chain of 9k preferentially forms an intramolecular hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramolecular hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of 9k in monkeys. On the basis of its profile, compound 9k has been selected as a candidate for clinical trials and it is expected that it will provide a new class of potential therapeutic agents for the clinical treatment of a variety of sex-hormone-dependent diseases.

Investigating Structural Changes Induced By Nucleotide Binding to RecA Using Difference FTIR

Nucleotide binding to RecA results in either the high-DNA affinity form (Adenosine 5′-triphosphate (ATP)-bound) or the more inactive protein conformation associated with a lower affinity for DNA (Adenosine 5′-diphosphate (ADP)-bound). Many of the key structural differences between the RecA-ATP and RecA-ADP bound forms have yet to be elucidated. We have used caged-nucleotides and difference FTIR in efforts to obtain a comprehensive understanding of the molecular changes induced by nucleotide binding to RecA. The photochemical release of nucleotides (ADP and ATP) from biologically inactive precursors was used to initiate nucleotide binding to RecA. Here we present ATP hydrolysis assays and fluorescence studies suggesting that the caged nucleotides do not interact with RecA before photochemical release. Furthermore, we now compare difference spectra obtained in H 2O and D 2O as our first attempt at identifying the origin of the vibrations influenced by nucleotide binding. The infrared data suggest that unique α-helical, β structures, and side chain rearrangements are associated with the high- and low-DNA affinity forms of RecA. Difference spectra obtained over time isolate contributions arising from perturbations in the nucleotide phosphates and have provided further information about the protein structural changes involved in nucleotide binding and the allosteric regulation of RecA.

Scyptolin A and B, cyclic depsipeptides from axenic cultures of Scytonema hofmanni PCC 7110

Two novel cyclic depsipeptides were isolated from axenic cultures of the terrestrial cyanobacterium Scytonema hofmanni PCC 7110 and designated scyptolin A and B. Amino acid analyses in context with mass and 1H/ 13C NMR spectroscopies revealed a composition typical for heterologous cyanopeptolins but containing the uncommon residue 3′-chloro- N-methyl-Tyr (cmTyr) and a unique sidechain. Scyptolin A and B both consist of the N-acylated peptide But 1-Ala 2-Thr 3-Thr 4-Leu 5-Ahp 6 (3-amino-6-hydroxy-2-oxo-1-piperidine)-Thr 7-cmTyr 8-Val 9, which forms a 19-membered ring by esterification of the carboxyl of Val 9 with the hydroxyl of Thr 4. In scyptolin B, the hydroxyl of the Thr 3 residue is additionally esterified with N-butyroyl-Ala. Both scyptolin A and B exhibit selective inhibition of porcine pancreatic elastase in vitro with IC 50 values of 3.1 μg/ml.

In vitro antibacterial activity and mechanism of action of J-111,225, a novel 1beta-methylcarbapenem, against transferable IMP-1 metallo-beta-lactamase producers.

IMP-1 beta-lactamase, a class B zinc metallo-enzyme encoded by the transferable bla(IMP) gene, is known to confer high-level resistance to carbapenems as well as to penicillins and cephalosporins. J-111, 225 is a novel 1beta-methylcarbapenem with a structurally unique side chain comprising a trans-3,5-disubstituted pyrrolidinylthio moiety at the C2 position. It inhibited 17 Serratia marcescens and two Pseudomonas aeruginosa IMP-1-producing clinical isolates at a concentration of 32 mg/L (range 4-32 mg/L). It showed synergy with imipenem against IMP-1-producing S. marcescens BB5886 and P. aeruginosa GN17203 with minimal FIC indices of 0.38 and 0.5, respectively. J-111,225 was more resistant than imipenem to hydrolysis by class B metallo-beta-lactamases. In kinetic studies, J-111,225 inhibited the IMP-I enzyme with a K(i) of 0.18 microM when imipenem was used as a substrate. In contrast, J-111,225 was the substrate for hydrolysis by other class B beta-lactamases such as Bacteroides fragilis CcrA, Stenotrophomonas maltophilia L1 and Bacillus cereus type II enzyme with respective K(m) values of 11, 10 and 148 microM. The greater antibacterial activity of J-111,225 against IMP-1-producing bacteria may result from its unique interaction with the beta-lactamase.

In vitro activities of novel trans-3,5-disubstituted pyrrolidinylthio-1beta-methylcarbapenems with potent activities against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

The in vitro activities of the novel 1beta-methylcarbapenems J-111, 225, J-114,870, and J-114,871, which have a structurally unique side chain that consists of a trans-3,5-disubstituted 5-arylpyrrolidin-3-ylthio moiety at the C-2 position, were compared with those of reference antibiotics. Among isolates of both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCoNS), 90% were inhibited by J-111,347 (prototype), J-111,225, J-114,870, and J-114,871 at concentrations of 2, 4, 4, and 4 microgram/ml (MICs at which 90% of isolates are inhibited [MIC(90)s]), respectively, indicating that these agents were 32- to 64-fold more potent than imipenem, which has an MIC(90) of 128 microgram/ml. Although these drugs were less active in vitro than vancomycin, which had MIC(90)s of 1 and 2 microgram/ml for MRSA and MRCoNS, respectively, the new carbapenems displayed better killing kinetics than vancomycin. The potent anti-MRSA activity was ascribed to the excellent affinities of the new carbapenems for penicillin-binding protein 2a of MRSA. Since the new carbapenems also exhibited good activity against gram-positive and -negative bacteria including clinically important pathogens such as penicillin-resistant Streptococcus pneumoniae, Haemophilus influenzae, members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Clostridium difficile, as well as MRSA, the novel carbapenems are worthy of further evaluation.

Negative ion postsource decay time-of-flight mass spectrometry of peptides containing acidic amino acid residues.

Acidic peptides have been studied by negative ion postsource decay (PSD) matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. The peptides contained from 5 to 16 residues and were chosen on the basis of their patterns of the acidic residues. Using typical MALDI sample preparation techniques employing an acidic matrix, gastrin I (1-14), and epidermal mitosis inhibiting pentapeptide yielded much larger deprotonated ion signals, [M - H]-, than protonated ions, [M + H]+. This may be due to their absence of basic residues, coupled with their arrays of acidic residues. The PSD fragmentation of the peptide negative ions showed that an array of acidic residues, as in gastrin I (1-14), yielded simple spectra containing mainly backbone cleavage ions from the C-terminus. Hirudin (54-65), which contains two sets of two consecutive Glu residues, and fibrinopeptide A and fibrinopeptide B, with isolated acidic residues, also showed backbone cleavages as common fragment ions. In addition, the two sets of isolated consecutive amino acid residues in Cys(Bzl)84-CD4 (81-92) and hirudin (54-56) yielded internal ions from the cleavages at the (O=C)-NH bond between the acidic residues. Also observed were ions with unique side chain losses, such as the loss of C6H4O from a tyrosine residue and SCH2C6H5 and CH2C6H5 from a benzylated cysteine residue. Compared to the positive mode, the negative-ion PSD yielded fewer fragments which usually involved only one type of backbone cleavage (e.g., [Yn - H2O]-). These simple spectra aided interpretation. Overall, the acidic peptides studied yielded negative ion PSD spectra that were useful for peptide sequencing.

Curious structure in "canonical" alanine-based peptides.

We have performed all atom simulations of blocked peptides of the form (AAXAA)3, where X = Gln, Asn, Glu, Asp, Arg, and Lys with explicit water molecules to examine the interactions between side chains spaced i,i-5 in the sequence. Although side chains in this i,i-5 arrangement are commonly believed to be noninteracting, we have observed the formation of unusual i,i-5 main chain hydrogen bonding in such sequences with positively charged residues (Lys) as well as polar uncharged groups (Gln). Our results are consistent with the unusual percentage of hydrogen bonding curves produced by amide exchange measurements on the well-studied sequence acetyl-(AAQAA)3-amide in water (Shalongo, W., Dugad, L., Stellwagen, E. J. Am. Chem. Soc. 116:8288-8293, 1994). Analysis of our simulations indicated that the glutamine side chain showed the greatest propensity to support pi helix formation and that the i,i-5 intramolecular hydrogen bonds were stabilized by water-bridging side chain interactions. This intermittent formation of the unusual pi helix structure was observed for up to 23% of the total simulation time in some residues in (AAQAA)3. Control studies on peptides with glutamine side chains spaced i,i-3, i,i-4 and i,i-6 did not reveal similar unique structures, providing stronger evidence for the unique role side chain interactions with i,i-5 spacing.

Structure of the LexA repressor-DNA complex probed by affinity cleavage and affinity photo-cross-linking.

The structure of the complex of full-length Escherichia coli LexA repressor with a consensus operator DNA fragment has been probed by affinity photo-cross-linking and affinity cleavage. These methods allow the determination of approximate intermolecular distances between a given protein residue and a base or sugar moiety within the operator. In a first step unique cysteine residues were introduced in positions 7, 28, 38, or 52 of the protein. In all four cases, the original amino acid was an arginine. The four amino acids in these positions were expected to be situated on the surface of LexA interacting with DNA, as inferred from the structure of the LexA DNA binding domain [Fogh et al. (1994) EMBO J. 13, 3936-3944]. In a second step, these unique cysteine side chains of the purified proteins were chemically modified either with 4-azidophenacyl bromide or with S-(2-pyridylthio)cysteaminyl-EDTA. The first set of derivatives gives rise to UV-induced cross-linking which may be revealed by alkali/heat treatment; the second leads to direct DNA cleavage in the proximity of the derivatized amino acid. To reduce hydroxyl radical diffusion, the EDTA-iron cleavage reactions were done in the presence of high amounts of glycerol. The results indicate that amino acids 7 and 52 are near nucleotide pairs 8-12 of the operator and that amino acids 28 and 36 of LexA are near nucleotide pairs 5-8 of the operator. The results unambiguously define the orientation of the LexA DNA binding domain relative to the operator and provide support for the model of the LexA-operator complex proposed by Knegtel et al. [(1995) Proteins 21, 226-236]. Ethylation interference experiments further suggest that Arg-7 contacts the phosphate group between nucleotides 8 and 9 as predicted by the model.

Raman spectroscopy of the Ff gene V protein and complexes with poly(dA): nonspecific DNA recognition and binding.

Raman spectra of crystals and solutions of the single-stranded DNA binding protein of bacteriophage Ff (gene V protein, gVp) and of solution complexes of gVp with single-stranded poly-(deoxyadenylic acid) [poly(dA)] reveal the following: (i) The gVp secondary and tertiary structures are similar in solution and in the crystal and are dominated by beta-sheet domains, in agreement with NMR and X-ray findings. (ii) Subunit conformation and side chain environments of gVp are virtually unchanged over a wide range of salt concentration (0 < [NaCl] < 100 mM); however, the solution conformation of poly(dA) exhibits sensitivity to added salt. The perturbed Raman markers indicate subtle changes in helix backbone geometry with accompanying small differences in base stacking as the concentration of NaCl is changed. (iii) In complexes with poly(dA), neither the conformation of gVp nor its side chain environments are altered significantly in comparison to the free protein. This is the case at both high salt (nucleotide-to-subunit binding stoichiometry n = 4) and low salt (n = 3). (iv) The Raman signature of poly(dA) undergoes small perturbations upon gVp binding, indicative of small changes in base stacking and phosphodiester backbone conformation. The present results show that the different stoichiometric binding modes of gVp to poly(dA) are accomplished without significant changes in gVp subunit structure and with only modest changes in the single-stranded poly(dA) ligand. This contrasts sharply with sequence-specific double-stranded DNA binding proteins, such as the phage lambda and D108 repressors, which undergo substantial structural changes upon DNA binding, and which also alter more dramatically the Raman fingerprints of their DNA target sites. Thus, nonspecific and specific nucleic acid recognition modes are distinguishable by Raman spectroscopy. The Raman signature of gVp also allows examination of hydrogen bonding interactions of unique side chains within the hydrophobic core (cysteine 33) and at the binding interface (tyrosine 41). These are discussed in relation to the recently published gVp crystal structure.

Pharmacokinetics of desogestrel

A synthetic form of desogestrel, a gonane progestin, was developed because desogestrel's enhanced selectivity eliminates adverse, androgen-dependent, metabolic effects at contraceptive doses. Desogestrel is rapidly and completely metabolized in the liver and gut wall to 3-keto-desogestrel, which is the active metabolite mediating the progestin effects. Because of its unique 11-methylene side chain, desogestrel cannot be metabolized to any other known progestin, nor is desogestrel a naturally occurring metabolite of any other progestin. The pharmacokinetic parameters of 3-keto-desogestrel are generally comparable with those of levonorgestrel and norethindrone. Therefore any differences in pharmacologic activities must be attributed to differences in intrinsic activities. Unlike gestodene, 3-keto-desogestrel has a lower affinity for sex hormone-binding globulin, which results in markedly lower plasma levels after administration. After oral administration of 150 micrograms of desogestrel, plasma levels are less than half the levels of gestodene after an oral dose of 75 micrograms.

Chemistry of the new immunosuppressant KH-1060: new synthons and x-ray evidence for unique side-chain geometry

The new vitamin D analog KH-1060 has immunosuppressive activity greater than of cyclosporin A. We report a new CD synthon 4 for the vitamin D analog KH-1060 and the synthesis and x-ray structure of related cholesterol derivative 15. Williamson ether synthesis provides a route to this class of compound using a new CD intermediate 8. The x-ray structure of 14 suggests that the immunosuppressive activity of KH-1060 may lie in its unique steroid side chain geometry.

Biosynthetic studies of marine lipids. 37. Enzymatic desaturation of 24(S)-methylcholesterol to 23,24-methylenecholesterol, norficisterol, and norhebesterol. Further evidence for a unified biosynthesis of marine sterols with unique side chains

Biosynthetic studies of marine lipids. 37. Enzymatic desaturation of 24(S)-methylcholesterol to 23,24-methylenecholesterol, norficisterol, and norhebesterol. Further evidence for a unified biosynthesis of marine sterols with unique side chains

Pigments of fungi. Part 11. (+)-Austrocorticin, austrocorticinic acid, austrocorticone, and related pigments; the first naturally occurring anthraquinones derived from a propionate-triggered octaketide

The anthraquinones (7), (9), (11), (13), (15), and (17) have been isolated from the orange fruit bodies of an Australian toadstool belonging to the genus Dermocybe. Five of these six pigments bear a unique C2 side chain at C-3 in the anthraquinone nucleus, the biogenetic origin of which has been studied by feeding 13C labelled precursors to young toadstools. High specific incorporation of isotope from sodium [3-13C]propionate into the C-3′ methyl group of pigments (7), (11), (13), (15), and (17) indicates that a propionate ‘starter’ effect is operating. The sixth pigment (9) is derived in the same organism by ‘normal’ acetate-triggered octaketide assembly.

アスボキシシリン分解物の研究(第1報)アスボキシシリンの加水分解系分解物

Concerning the decomposition of a novel semisynthetic penicillin, aspoxicillin (ASPC) in aqueous solution, several labile products were isolated and their structures elucidated. The stepwise rearrangements of the penam ring were recognized and they were similar to the known decomposition system about the practical penicillins, in spite of the unique 6-acyl side chain of ASPC.

The carbapenems: new broad spectrum -lactam antibiotics

The carbapenems differ from the penicillins (penams) in having an unsaturated bond between C2 and C3 and a carbon atom replacing sulphur at position 1 of the thiazolidine ring. The various carbapenems differ primarily in the configuration of the side chains at C2 and C6. Carbapenems include the thienamycins, olivanic acids, carpetimycins, asparenomycins, pluracidomycins, and other natural and semi-synthetic compounds. Carbapenems vary in their stability and resistance to beta-lactamases, ability to inhibit and to induce beta-lactamases, and in-vitro spectra of activity. Many are highly unstable in solution. Some are degraded by mammalian dehydropeptidases in vivo. The hydroxyethyl side chain in the alpha or trans-configuration at C6 in thienamycin provides striking resistance to beta-lactamases, but this compound is highly unstable in concentrated solution and the solid state. The N-formimidoyl derivative of thienamycin (imipenem) is more stable in solution and has broad-spectrum activity against aerobic and anaerobic bacteria. However, imipenem is not stable to renal dehydropeptidases and its degradation products are nephrotoxic in certain animals. It is thus administered with the dehydropeptidase inhibitor cilastatin. High serum levels of imipenem (especially in patients with renal failure and central nervous system disease) have been associated with seizures. The drug is therefore not appropriate for meningitis. Meropenem is a new carbapenem which has the same side chain as imipenem at C6. Its unique side chain at C2 assures a broad spectrum of activity which includes Pseudomonas aeruginosa and other aerobic and anaerobic organisms. Only Ps. (Xanthomonas) maltophilia is generally resistant. This species is resistant also to imipenem.(ABSTRACT TRUNCATED AT 250 WORDS)