ABSTRACT Mannopeptimycins α, β, γ, δ, and ε are new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98. Mannopeptimycins γ, δ, and ε, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin ε was the most active component against methicillin-resistant staphylococci and vancomycin-resistant enterococci (MICs, 2 to 4 μg/ml for staphylococci and streptococci and 4 to 32 μg/ml for enterococci), while mannopeptimycins γ and δ were two- to fourfold less active. Mannopeptimycins α and β, which lack the isovaleryl substitution and the disaccharide moiety, respectively, had poor antibacterial activities. The in vivo efficacies of the mannopeptimycins in Staphylococcus aureus mouse protection studies paralleled their in vitro activities. The median effective doses of mannopeptimycins γ, δ, and ε were 3.8, 2.6, and 0.59 mg/kg of body weight, respectively. The mannopeptimycins were inactive against cell wall-deficient S. aureus and caused spheroplasting of Escherichia coli imp similar to that observed with penicillin G in an osmotically protective medium. Mannopeptimycin δ rapidly inhibited [3H]N-acetylglucosamine incorporation into peptidoglycan in Bacillus subtilis and had no effect on DNA, RNA, or protein biosynthesis. On the basis of the observations presented above, an effect on cell wall biosynthesis was suggested as the primary mode of action for mannopeptimycin δ. The mannopeptimycins were inactive against Candida albicans, did not initiate hemolysis of human erythrocytes, and did not promote potassium ion leakage from E. coli imp, suggesting a lack of membrane damage to prokaryotic or eukaryotic cells.

BACKGROUND:Emergence of antibiotic resistant Helicobacter pylori has necessitated the identification of alternate therapies for the treatment of this infection.AIM:To assess the in vitro efficacy of two investigational agents: DMG-MINO CL 344 (a N,N-dimethylglycylamido derivative of minocycline), and davercin, a cyclic carbonate of erythromycin A as compared to older antibiotics (clarithromcyin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, cefixime) against clinical isolates of H. pylori.METHODS:Testing was performed using the agar dilution method approved by the NCCLS subcommittee on antimicrobial susceptibility testing, Helicobacter pylori working group. Under these guidelines, Mueller-Hinton agar containing 5% aged sheep blood was used. All incubations were done under CampyPak Plus conditions for 72 h at 37 degrees C. The drug concentrations in the agar ranged from 0.016 to 16 microg/mL. Twenty-one clarithromycin-resistant and 16 clarithromycin-susceptible clinical isolates of H. pylori obtained from patients with duodenal ulcer were used. H. pylori ATCC 43504 was used as the control in all determinations.RESULTS:Against clarithromycin susceptible isolates, all antimicrobial agents except the fluoroquinolones were highly effective. Against clarithromycin-resistant H. pylori, the MIC50/MIC90 values showed that the tetracyclines and cefixime were the most efficacious agents. The fluoroquinolones and macrolides were ineffective. Macrolide cross-resistance was detected.CONCLUSION:Macrolide cross-resistance prevents the use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients.

ABSTRACT The 9- t -butylglycylamido derivative of minocycline (TBG-MINO) is a recently synthesized member of a novel group of antibiotics, the glycylcyclines. This new derivative, like the first glycylcyclines, the N , N -dimethylglycylamido derivative of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity against bacterial isolates containing the two major determinants responsible for tetracycline resistance: ribosomal protection and active efflux. The in vitro activities of TBG-MINO and the comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 μg/ml, showed good activity against strains expressing tet (M) (ribosomal protection), tet (A), tet (B), tet (C), tet (D), and tet (K) (efflux resistance determinants). TBG-MINO exhibited similar activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci (MICs at which 90% of strains are inhibited, ≤0.5 μg/ml). TBG-MINO exhibited activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to tetracycline and minocycline. The in vivo protective effects of TBG-MINO were examined against acute lethal infections in mice caused by Escherichia coli , S. aureus , and Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by S. aureus including MRSA strains and strains containing tet (K) or tet (M) resistance determinants (median effective doses [ED 50 s], 0.79 to 2.3 mg/kg of body weight). TBG-MINO demonstrated efficacy against infections caused by tetracycline-sensitive E. coli strains as well as E. coli strains containing either tet (M) or the efflux determinant tet (A), tet (B), or tet (C) (ED 50 s, 1.5 to 3.5 mg/kg). Overall, TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents. The in vivo protective effects, especially against infections caused by resistant bacteria, corresponded with the in vitro activity of TBG-MINO.

The biochemical properties of tetrahydrofuranyl (THF) carbapenems, carbapenems with THF substituents, were evaluated with respect to enzyme stability, binding to penicillin-binding proteins (PBPs), and penetration into gram-negative organisms. THF carbapenems showed increased stability to hog renal dehydropeptidases (DHPs) compared to that of imipenem or meropenem and were more stable to human DHP than imipenem (<10% hydrolysis compared to that for imipenem). THF carbapenems were stable to hydrolysis by all serine beta-lactamases tested. CL 191,121, a prototype THF carbapenem, was more stable to hydrolysis by carbapenem-hydrolyzing serine beta-lactamases such as IMI-1 and Sme-1 than imipenem, with a relative k(cat) value of <20% for imipenem. Similar to imipenem and meropenem, THF carbapenems were not stable to the metallo beta-lactamases CcrA and L1. However, CL 191,121 bound to all Staphylococcus aureus PBPs at concentrations that were less than or equal to the MICs. The THF carbapenems bound to PBPs from Escherichia coli and Pseudomonas aeruginosa, with the highest affinities being for PBPs 2 and 4, as noted with imipenem. The affinities for PBPs 1a and 1b in E. coli were reduced for the THF carbapenems compared to that for imipenem, even though the MICs of the THF carbapenems for E. coli strains were lower than those of imipenem. The penetrability of the THF carbapenems into Serratia marcescens S6, which produces the Sme-1 carbapenem-hydrolyzing beta-lactamase, was 2.4 to 7.8 times less than that of imipenem. Compounds CL 190,294 and CL 188,624 showed good penetrability, with permeability coefficient values comparable to those of the rapidly penetrating agents cephaloridine, imipenem, meropenem, and biapenem. Decreased penetration into wild-type P. aeruginosa was suggested by the high MICs of the THF carbapenems (MICs, 16 to 32 microg/ml), despite equivalent or better binding to P. aeruginosa PBPs than that of imipenem. However, the MICs of the THF carbapenems for wild-type P. aeruginosa compared to that for an OprD2 mutant generally varied no more than 2-fold, but those of imipenem and other carbapenems differed 16-fold. These data indicated that THF carbapenems do not appear to enter through protein OprD2. In conclusion, the THF carbapenems exhibited stability to hydrolysis by renal DHPs and serine beta-lactamases, exhibited strong binding to essential PBPs from E. coli and S. aureus, and penetrated gram-negative enteric bacteria at rates comparable to those for meropenem and biapenem.

ABSTRACT CL 188,624, CL 190,294, and CL 191,121 are novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems. The in vitro antibacterial activities of these THF carbapenems were evaluated and compared with those of biapenem, imipenem, and meropenem against 554 recent clinical isolates obtained from geographically distinct medical centers across North America. The antibacterial activities of the THF carbapenems were equivalent to that of biapenem, and the THF carbapenems were slightly more active than imipenem and less active than meropenem against most of the members of the family Enterobacteriaceae but lacked significant activity against Pseudomonas isolates. In general, CL 191,121 was two- to fourfold more active than CL 188,624 and CL 190,294 against the staphylococcal and enterococcal isolates tested. CL 191,121 was twofold less active than imipenem against methicillin-susceptible staphylococci and was as activity as imipenem against Enterococcus faecalis isolates. Biapenem and meropenem were two- and fourfold less active than CL 191,121, respectively, against the methicillin-susceptible staphylococci and E. faecalis . All the carbapenems displayed equivalent good activities against the streptococci. Biapenem was slightly more active than the other carbapenems against Bacteroides fragilis isolates. Time-kill curve studies demonstrated that the THF carbapenems were bactericidal in 6 h against Escherichia coli and Staphylococcus aureus isolates. The postantibiotic effect exerted by CL 191,121 was comparable to or slightly longer than that of imipenem against isolates of S. aureus , E. coli , and Klebsiella pneumoniae.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A series of twelve highly active aminomethyl-THF 1β-methylcarbapenems 3a-1 were synthesized. Of these, carbapenems 3a-f demonstrated a spectrum of antimicrobial activity comparable to those of imipenem and meropenem with the exception of only moderate anti-pseudomonal activity. Most importantly, they demonstrated moderate intrinsic oral activity against an E. coli infection in mice.

Mono and bis double ester prodrugs of aminomethyl THF 1β-methylcarbapenems 1 were synthesized. Mono double ester derivatives (2, 4 and 7) did not demonstrate significantly improved oral activity due to the presence of the charged species. However, bis double ester derivatives (3 and 5) demonstrated enhanced oral activity.

Strain NRRL 12292T, which produces the bleomycin-like antibiotics LL-BO1208 alpha and LL-BO1208 beta, forms umbels consisting of chains of smooth-surface ovoid spores that are borne on verticils on the serial mycelia, indicating that it is a member of the verticillate group of the genus Streptomyces formerly classified in the genus Streptoverticillium. This strain was compared morphologically and physiologically to 54 other verticillate Streptomyces strains. The levels of DNA relatedness between strain NRRL 12292T and 34 other verticillate Streptomyces strains, including strains representing at least 19 genetic species clusters, were also determined. Strain NRRL 12292T is morphologically and physiologically distinct from the other verticillate strains studied, particularly because of the straw yellow color of its aerial mycelia and spore mass. DNA hybridization data support the uniqueness of this strain, since the levels of DNA relatedness between NRRL 12292T and the other verticillate strains used in this study were low. Our data support designation of a new species, Streptomyces stramineus, whose type strain is NRRL 12292.

ABSTRACTA series of novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight againstEscherichia coliand 0.9 mg/kg againstStaphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs withl-amino acids demonstrated improved efficacy after oral administration, while thedforms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of <1 mg/kg against infections caused byS. aureus,E. coli,Enterobacter cloacae, or penicillin-susceptibleStreptococcus pneumoniaewere obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious againstMorganella morganii,Serratia marcescens, penicillin-resistantS. pneumoniae, extended-spectrum β-lactamase-producingKlebsiella pneumoniae, andE. coliinfections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to >32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.

The in vitro activity of piperacillin alone or titrated with a constant concentration of 4 mu g/ml tazobactam was evaluated against 3962 baseline pathogens isolated from 1899 patients enrolled in 9 clinical trial studies in North America. Tazobactam increased susceptibility rates of piperacillin for Enterobacteriaceae from 81% to 96%, Staphylococcus (methicillin susceptible) spp. from 6% to 100%, Bacteroides fragilis group from 79% to > 99% and Haemophilus from 85% to 98%. The excellent activity of piperacillin against Pseudomonas, Streptococcus and Enterococcus was maintained in the presence of tazobactam. Overall piperacillin/tazobactam had better activity than ticarcillin/clavulanic acid, ceftazidime, and in general equaled the activity of imipenem. The excellent in vitro, extended-spectrum activity of piperacillin/tazobactam suggests its utility for various infections.

A series of 9-(acylamino)doxycycline derivatives has been prepared. These analogs exhibit good activity against both tetracycline sensitive and tetracycline resistant Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria that are encoded with the efflux and ribosomal resistance gene factors. N,N-Dialkylglycylamido derivatives possessed the highest activity. Replacement of glycine moiety with other amino acids did not further enhance the activity.

This report describes the discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". These agents are notable for their activity against a broad spectrum of tetracycline-susceptible and -resistant Gram-negative and Gram-positive aerobic and anaerobic bacteria possessing various classes of tetracycline-resistant determinants [tet B (efflux), tet M (ribosomal protection)]. The design and synthesis of a number of 7-substituted 9-substituted-amido 6-demethyl-6-deoxytetracyclines are described.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Journal Article Susceptibility of Anaerobes in Phase 3 Clinical Studies of Piperacillin/Tazobactam Get access N. V. Jacobus, N. V. Jacobus From the Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York Reprints or correspondence: Nilda V. Jacobus, Medical Research Division, American Cyanamid Company, Lederle Laboratories (200/3301A), Pearl River, New York 10965. Search for other works by this author on: Oxford Academic PubMed Google Scholar F. W. Immermann, F. W. Immermann From the Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar J. M. Gupte, J. M. Gupte From the Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar R. T. Testa R. T. Testa From the Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar Clinical Infectious Diseases, Volume 16, Issue Supplement_4, June 1993, Pages S344–S348, https://doi.org/10.1093/clinids/16.Supplement_4.S344 Published: 01 June 1993

N,N-Dimethylglycylamido (DMG) derivatives of minocycline and 6-demethyl-6-deoxytetracycline are new semisynthetic tetracyclines referred to as the glycylcyclines. The in vitro activities of the glycylcyclines were evaluated in comparison with those of minocycline and tetracycline against strains carrying characterized tetracycline resistance determinants and against 995 recent clinical isolates obtained from geographically distinct medical centers in North America. The glycylcyclines were active against tetracycline-resistant strains carrying efflux [tet(A), tet(B), tet(C), and tet(D) in Escherichia coli and tet(K) in Staphylococcus aureus] and ribosomal protection [tet(M) in S. aureus, Enterococcus faecalis, and E. coli)] resistance determinants. Potent activity (MIC for 90% of strains, < or = 0.5 microgram/ml) was obtained with the glycylcyclines against methicillin-susceptible and methicillin-resistant S. aureus, E. faecalis, Enterococcus faecium, and various streptococcal species. The glycylcyclines exhibited good activity against a wide diversity of gram-negative aerobic and anaerobic bacteria, most of which were less susceptible to minocycline and tetracycline. The activities of the glycylcyclines against most organisms tested were comparable to each other. The in vivo efficacies of the glycylcyclines against acute lethal infections in mice when dosed intravenously were reflective of their in vitro activities. The glycylcyclines had efficacies comparable to that of minocycline against infections with methicillin-susceptible and methicillin-resistant S. aureus strains, a strain carrying tet(K), and a tetracycline-susceptible E. coli strain but exceeded the effectiveness of minocycline against infections with resistant isolates, including strains harboring tet(M) or tet(B). Levels of DMG-6-deoxytetracycline in serum were higher and more sustained than those of DMG-minocycline or minocycline. Our results show that the glycylcyclines have potent in vitro activities against a wide spectrum of gram-positive and gram-negative, aerobic and anaerobic bacteria, including many resistant strains. On the basis of their in vitro and in vivo activities, the glycylcyclines represent a significant advance to the tetracycline class of antibiotics and have good potential value for clinical efficacy.

Nitrosation, carbamoylation or acylation of the glycopeptide antibiotics eremomycin or vancomycin produced series of derivatives substituted at the N-terminus of the peptides. Though the modified amino group in these derivatives is not capable of protonation, N-nitroso derivatives retain antibacterial activity in vitro and in vivo. N-Carbamoyleremomycin has low activity, and N-Cbz-eremomycin and N-Boc-eremomycin are devoid of antibacterial activity, both in vitro and in vivo.