Structure-activity relationships of globomycin analogues as antibiotics

Globomycin (1a), a signal peptidase II inhibitor, and its derivatives show potent antibacterial activity against Gram-negative bacteria. The synthesis and antimicrobial activity of novel globomycin analogues are reported. The hydroxyl group in the L-Ser residue was essential for the antimicrobial activity and the length of the alkyl side chain greatly influenced the activity. In addition, derivatives that had a modified cyclic core exhibited weak activity. One of the analogues showed a wider antimicrobial spectrum, effective against not only Gram-negative but also Gram-positive bacteria.     

Structure-activity relationship study of anoplin.

Anoplin is a decapeptide amide, GLLKRIKTLL-NH2 derived from the venom sac of the solitary spider wasp, Anoplius samariensis. It is active against Gram-positive and Gram-negative bacteria and is not hemolytic towards human erythrocytes. The present paper reports a structure-activity study of anoplin based on 37 analogues including an Ala-scan, C- and N-truncations, and single and multiple residue substitutions with various amino acids. The analogues were tested for antibacterial activity against both S. aureus ATCC 25923 and E. coli ATCC 25922, and several potent antibacterial analogues were identified. The cytotoxicity of the analogues against human erythrocytes was assessed in a hemolytic activity assay. The antibacterial activity and selectivity of the analogues against S. aureus and E. coli varied considerably, depending on the hydrophobicity and position of the various substituted amino acids. In certain cases the selectivity for Gram-positive and Gram-negative bacteria was either reversed or altogether eliminated. In addition, it was generally found that antibacterial activity coincided with hemolytic activity.     

Design,synthesis and biological evaluation of simplified analogues of the RNA polymerase inhibitor etnangien

Novel simplified analogues of the potent RNA polymerase inhibitor etnangien were obtained by total synthesis and evaluated for antibacterial activity against Gram-positive bacteria and one Gram-negative bacterium.     

Optimization of globomycin analogs as novel gram-negative antibiotics

Discovery of novel classes of Gram-negative antibiotics with activity against multi-drug resistant infections is a critical unmet need. As an essential member of the lipoprotein biosynthetic pathway, lipoprotein signal peptidase II (LspA) is an attractive target for antibacterial drug discovery, with the natural product inhibitor globomycin offering a modestly-active starting point. Informed by structure-based design, the globomycin depsipeptide was optimized to improve activity against E. coli. Backbone modifications, together with adjustment of physicochemical properties, afforded potent compounds with good in vivo pharmacokinetic profiles. Optimized compounds such as 51 (E. coli MIC 3.1 μM) and 61 (E. coli MIC 0.78 μM) demonstrate broad spectrum activity against gram-negative pathogens and may provide opportunities for future antibiotic discovery.     

CP0569, a new broad-spectrum injectable carbapenem. Part 1: synthesis and structure-activity relationships

A series of 1beta-methylcarbapenems bearing an (imidazo[5,1-b]thiazolium-6-yl)methyl moiety, a 5,5-fused heterobicycle, at the C-2 position was synthesized and evaluated for in vitro antibacterial activities. CP0569 (1r) and its analogues showed potent antibacterial activities against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Gram-negative bacteria, including Pseudomonas aeruginosa. Moreover, CP0569 (1r) exhibited stronger antibacterial activity against MRSA and higher resistance to renal dehydropeptidase-1 (DHP-1) than any currently marketed carbapenems, that is, imipenem (IPM), panipenem (PAPM), and meropenem (MEPM).     

Synthesis and antibacterial activity evaluation of metronidazole–triazole conjugates

Synthesis and antibacterial activity of metronidazole–triazole conjugates are reported. Total 21 hybrid compounds have been synthesized with different substitution pattern on the triazole ring in order to study their influence on the antibacterial activity. These compounds demonstrated potent to weak antibacterial activity against Gram-positive, and Gram-negative bacteria. Six compounds have shown equal or better antibacterial activity against Gram-negative strains than the reference compound.     

CP6679, a new injectable cephalosporin. Part 1: synthesis and structure-activity relationships

A series of cephalosporins bearing a 5,5-fused ring system, an (imidazo[5,1-b]thiazolium-6-yl)methyl group, at the C-3 position were synthesized and evaluated for in vitro antibacterial activities. CP6679 (1s) and its analogues showed potent antibacterial activities against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa. They were also highly active against methicillin-resistant Staphylococcus aureus (MRSA). CP6679 (1s) showed more potent antibacterial activity than ceftazidime (CAZ) or cefpirome (CPR) against Pseudomonas aeruginosa and MRSA.     

Design,synthesis and antibacterial evaluation of novel AHL analogues

Two series of novel AHL analogues were designed, synthesized and evaluated for antibacterial activity under cell membrane conditions in vitro. Analogues 4a–c and 4g–m presented potent activity against Gram-positive bacteria. Especially the analogue 4l exerted the most potent inhibition against Bacillus subtilis with MIC₅₀ value of 1.443 μg/ml. To our surprise, analogues 6a–c and 6g showed weak inhibition against Gram-negative bacteria with MIC₅₀ values ranging from 17.589 to 67.840 μg/ml. This was the first report about synthesis and antibacterial evaluation in vitro of AHL analogues containing dithioester linkage.     

Carbon–carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon–carbon linked pyrazolylphenyl analogues has been prepared. The -N-substituted methyl pyrazole (10) in the C3-linked series exhibited very good Gram-positive activity with MICs ≤0.5–1 μg/mL and moderate Gram-negative activity with MICs=2–8 μg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found to have potent in vivo activity with an ED₅₀=1.9 mg/kg. β-Substitution at the C3-linked pyrazole generally results in a loss of activity. The C4-linked pyrazoles are slightly more potent than their counterparts in the C3-linked series. Most of the analogues in the C4-linked series exhibited similar levels of activity in vitro, but lower levels of activity in vivo than 10. In addition, incorporation of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole analogue (34) exhibited an exceptional in vitro activity with MICs of ≤ 0.06–0.25 μg/mL against Gram-positive pathogens and with MICs of 1 μg/mL against fastidious Gram-negative pathogens.     

Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents

The synthesis and antibacterial activity of heterocyclic methylsulfone hydroxamates is presented. Compounds in this series are potent inhibitors of the LpxC enzyme, a key enzyme involved in the production of lipopolysaccharide (LPS) found in the outer membrane of Gram-negative bacteria. SAR evaluation of compounds in this series revealed analogs with potent antibacterial activity against challenging Gram-negative species such as Pseudomonas aeruginosa and Klebsiella pneumoniae.     

Structure-guided discovery of 1,3,5-triazine–pyrazole conjugates as antibacterial and antibiofilm agent against pathogens causing human diseases with favorable metabolic fate

Impressed by the exceptional antibacterial activity exhibited by our earlier designed molecules originating from 1,3,5-triazine, the present study was undertaken to synthesize a novel series of 1,3,5-triazine–pyrazole conjugates to bring diversity around the core skeleton. The target analogues showed potent antibacterial activity against tested Gram-positive and Gram-negative microorganisms. The toxicity and metabolic site prediction studies were also held out to set an effective lead candidate for the future antibacterial drug discovery initiatives.     

Design, synthesis and biological evaluation of simplified side chains of the macrolide antibiotic etnangien

Novel simplified side chains of the potent RNA polymerase inhibitor etnangien were designed, synthesized and evaluated for antibacterial activity against Gram-positive bacteria and one Gram-negative bacterium.     

Novel hybrids of 15-membered 8a- and 9a-azahomoerythromycin A ketolides and quinolones as potent antibacterials

A series of novel 6-O-substituted and 6,12-di-O-substituted 8a-aza-8a-homoerythromycin A and 9a-aza-9a-homoerythromycin A ketolides were synthesized and evaluated for in vitro antibacterial activity against a panel of representative erythromycin-susceptible and erythromycin-resistant test strains. Another series of ketolides based on 14-membered erythromycin oxime scaffold was also synthesized and their antibacterial activity compared to those of 15-membered azahomoerythromycin analogues. In general, structure-activity studies have shown that 14-membered ketolides displayed favorable antibacterial activity in comparison to their corresponding 15-membered analogues within 9a-azahomoerythromycin series. However, within 8a-azahomoerythromycin series, some compounds incorporating a ketolide combined with either quinoline or quinolone pharmacophore substructures showed significantly potent activity against a variety of erythromycin-susceptible and macrolide-lincosamide-streptogramin B (MLS(B))-resistant Gram-positive pathogens as well as fastidious Gram-negative pathogens. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens and display hitherto unprecedented in vitro activity against the constitutively MLS(B)-resistant strain of Staphylococcus aureus. In addition, they also represent an improvement over telithromycin (2) and cethromycin (3) against fastidious Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis.     

Non-iron metalloporphyrins: potent antibacterial compounds that exploit haem/Hb uptake systems of pathogenic bacteria

A new group of potent antibacterial compounds, non-iron metalloporphyrins (MPs), is described. MPs possess a strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and mycobacteria. Anaerobically grown bacteria and microorganisms that do not respire and/or express haem uptake systems were resistant to MPs. Antibacterial activity of MPs was not affected by known antibiotic resistance mechanisms operating in bacteria. The most potent MP against Y. enterocolitica, methicillin-resistant S. aureus and M. smegmatis was gallium protoporphyrin IX (Ga-PPIX). When tested alone, Ga ions and metal-free porphyrins had approximately 100-fold higher minimum inhibitory concentration (MIC) values for these organisms. Ga-PPIX was not degraded by MP-sensitive bacteria, indicating that the whole molecule is responsible for antibacterial activity. MPs are antibacterial 'Trojan horses', as they exploit haem transport systems of Gram-negative bacteria as portals of entry into the cell. Bacterial mutants in superoxide dismutases, catalases and stationary-phase sigma factors were hypersensitive to Ga-PPIX. The extreme sensitivity of sod mutants to MPs and the requirement for active respiration for MP activity suggests that these compounds stimulate the production of reactive oxygen radicals in bacteria. Ga-PPIX was not toxic to primary human fibroblasts, several established cell lines and experimental animals at concentrations > 100-fold higher than the MIC for sensitive bacteria.     

A novel insect defensin mediates the inducible antibacterial activity in larvae of the dragonfly Aeschna cyanea (Paleoptera, Odonata).

The injection of low doses of bacteria into the aquatic larvae of dragonflies (Aeschna cyanea, Odonata, Paleoptera) induces the appearance in their hemolymph of a potent antibacterial activity. We have isolated a 38-residue peptide from this hemolymph which is strongly active against Gram-positive bacteria and also shows activity against one of the Gram-negative bacteria which was tested. The peptide is a novel member of the insect defensin family of inducible antibacterial peptides, which had so far only been reported from the higher insect orders believed to have evolved 100 million years after the Paleoptera. Aeschna defensin is more potent than defensin from the dipteran Phormia, from which its structure differs in several interesting aspects, which are discussed in the paper.     

Synthesis and antibacterial activities of novel oxazolidinones having cyclic sulfonamide moieties

The synthesis of a new series of oxazolidinones having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone ring was investigated. A particular compound 15g having [1,2,5]thiadiazolidin-1,1-dioxide moiety showed the most potent antibacterial activity.     

The synthesis and antibacterial activity of totarol derivatives. Part 1: modifications of ring-C and pro-drugs.

A series of analogues of, and potential pro-drugs derived from, the potent antibacterial diterpene totarol (1) were synthesized in order to elucidate the minimum structural requirements for antibacterial activity and to seek compounds with good bioavailability in vivo. These analogues varied in the structural features of their aromatic rings and the prodrugs were O-glycosylated derivatives. They were tested in vitro against three gram-positive bacteria: beta-lactamase-positive and high level gentamycin-resistant Enterococcus faecalis, penicillin-resistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus (MRSA); and against the gram-negative multi-drug-resistant Klebsiella pneumoniae. None of the analogues was more potent than totarol itself, which is effective against these gram-positive bacteria at MIC values of 7 microM. The results were evaluated in terms of a structure-activity relationship and this showed that a phenolic moiety was essential for potent antibacterial activity. Amongst the pro-drugs, totaryl alpha-D-mannopyranoside (22) proved the most active in vitro (MIC 18 microM). The in vivo antibacterial activities of compounds 1, 22 and totarol beta-lactoside (23) were assessed in a mouse model of infection, but they were found to be ineffective. Compounds 1 and 22 were shown to be cytotoxic towards proliferating human cell cultures, CH 2983, HeLa, and MG 63, but only at concentrations of > 30 microM.     

Synthesis and antibacterial activities of novel oxazolidinones having spiro[2,4]heptane moieties

The synthesis of a new series of oxazolidinones having spiro[2,4]heptane moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the oxazolidinone ring was investigated. A particular compound Ih having fluoro group showed the most potent antibacterial activity.     

Effect of varying the 4'-position of arbekacin derivatives on antibacterial activity against MRSA and Pseudomonas aeruginosa

4'-Deoxy-4'-episubstituted arbekacin derivatives and 4'-epi-5-deoxy-5-episubstituted arbekacin derivatives were designed and synthesized. Arbekacin and 4'-epiarbekacin both displayed the same antibacterial activity against Staphylococcus aureus (including methicillin-resistant S. aureus (MRSA)) and Pseudomonas aeruginosa. The 4'-epi-5-deoxy-5-episubstituted arbekacin derivatives showed potent antibacterial activity. Among them, the antibacterial activity of 5,4'-diepiarbekacin was superior to that of arbekacin or 5-episubstituted arbekacin against Gram-positive and Gram-negative bacteria. The 6'-N-methyl derivative of the 5,4'-diepiarbekacin was effective against P. aeruginosa expressing an aminoglycoside-modifying enzyme AAC(6')-Ib.     

Antibacterial activity of ethanolic and aqueous extracts of Acacia aroma Gill. ex Hook et Arn

The purpose of the present study was to investigate the antibacterial activity of seven ethanolic extracts and three aqueous extracts from various parts (leaves, stems and flowers) of A. aroma against 163 strains of antibiotic multi-resistant bacteria. The disc diffusion assay was performed to evaluate antibacterial activity of the A. aroma crude extracts, against several Gram-positive bacteria (E. faecalis, S. aureus, coagulase-negative stahylococci, S. pyogenes, S. agalactiae, S. aureus ATCC 29213, E. faecalis ATCC 29212) and Gram-negative bacteria (E. coli., K. pneumoniae, P. mirabilis, E. cloacae, S. marcescens, M morganii, A. baumannii, P. aeruginosa, S. maltophilia, E. coli ATCC 35218, P. aeruginosa ATCC 27853, E. coli ATCC 25922). All ethanolic extracts showed activity against gram-positive bacteria. Among all obtained extracts, only leaf and flower fluid extracts showed activity against Gram-negative bacteria. Based on this bioassay, leaf fluid extracts tended to be the most potent, followed by flower fluid extracts. Minimal inhibitory concentration (MIC) values of extracts and antibiotics were comparatively determined by agar and broth dilution methods. Both extracts were active against S. aureus, coagulase-negative stahylococci, E. faecalis and E. faecium and all tested Gram-negative bacteria with MIC values from 0.067 to 0.308 mg/ml. In this study the minimal bactericidal concentration (MBC) values were identical or twice as high than the corresponding MIC for leaf extracts and four or eight times higher than MIC values for flower extracts. This may indicate a bactericidal effect. Stored extracts have similar antibacterial activity as recently obtained extracts. The A. aroma extracts of leaves and flowers may be useful as antibacterial agents against Gram- negative and Gram-positive antibiotic multi-resistant microorganisms.