Formadicins, new monocyclic beta-lactam antibiotics of bacterial origin. II. Isolation, characterization and structures

New monocyclic beta-lactam antibiotics, formadicins A, B, C and D, were isolated from the culture filtrate of Flexibacter alginoliquefaciens sp. nov. YK-49 by various types of column chromatography and preparative reverse-phase HPLC. Their structures were determined by spectroscopic analyses and degradation studies. They have a nocardicin-type skeleton and a formylamino group at the 3- or 12-position. Formadicins A and B each have a D-glucuronide moiety and give formadicins C and D, respectively, upon hydrolysis using beta-D-glucuronidase.     

Formadicins, new monocyclic beta-lactam antibiotics of bacterial origin. I. Taxonomy, fermentation and biological activities

A Gram-negative bacterium produces new monocyclic beta-lactam antibiotics with a formylamino substituent, named formadicins A, B, C and D. The producing bacterium was taxonomically characterized and designated as Flexibacter alginoliquefaciens sp. nov. YK-49. Formadicins have narrow antibacterial spectra. They are highly active against some species of Pseudomonas, Proteus and Alcaligenes. Of the four, formadicin C shows the most potent antibacterial activity. Several amino acids such as glycine, D-alanine and D-leucine were antagonistic against formadicins. Formadicins, especially formadicins A and C having the formylamino substituent bound to the 3-position of a beta-lactam nucleus, were highly resistant to hydrolysis by various types of beta-lactamases. Formadicins A and C showed affinity for penicillin-binding proteins (PBPs) 1A and 1B in Pseudomonas aeruginosa IFO 3080, but formadicin B and nocardicin A showed affinity only for PBP 1B. Formadicins A and C did not lyse Escherichia coli LD-2 solely at their MICs, but when combined with mecillinam each induced a rapid lysis of this organism.     

The bacterial envelope as a target for novel anti-MRSA antibiotics

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) are spreading worldwide, making the search for antibiotics directed against new targets a high priority. Drugs that anchor in the bacterial membrane (e.g. ceragenins and lipopeptides) or that target the bacterial membrane and proteic (lipoglycopeptides) or lipidic (glycodepsipeptides) cell wall precursors seem to have the most potential because they show a fast and extensive bactericidal effect and are probably less prone to select for resistance owing to the difficulty in modifying their targets in a way that is compatible with bacterial survival. The efficacy of lipopeptides and lipoglycopeptides has been demonstrated in the treatment of skin and skin structure infections, and bacteremia caused by resistant S. aureus. Ceragenins and glycodepsipeptides are restricted to topical applications because of their unsatisfactory safety profile. The mode of action, pharmacological and microbiological properties and target indications of these anti-MRSA agents, which function by disturbing membrane integrity, are reviewed in this article.     

Cephabacins, new cephem antibiotics of bacterial origin. I. Discovery and taxonomy of the producing organisms and fermentation

Three Gram-negative bacteria produce new cephem antibiotics, named cephabacins, with unique 3-side chains. Cephabacins include F group antibiotics with a 7-formylamino substituent and H group antibiotics without the substituent. The producing bacteria were taxonomically characterized and designated as Lysobacter lactamgenus sp. nov. YK-90 and Xanthomonas lactamgena sp. nov. YK-278 and YK-280.     

Cephabacin M1-6, new 7-methoxycephem antibiotics of bacterial origin. II. Isolation, characterization and structural determination

Six components of new cephem antibiotics, cephabacin M1-6, were isolated from the culture filtrate of Xanthomonas lactamgena YK-431 by various types of column chromatographies and preparative reverse-phase HPLC. Their structures were determined by spectroscopic analyses and degradation studies. They consist of 7-methoxydeacetylcephalosporin C as a nucleus and a tri- to heptapeptide including a new amino acid, which is bound at the 3-position with an ester bond.     

Protegrins: new antibiotics of mammalian origin

Protegrins and their derivatives are a new class of peptide antibiotics based on mammalian antimicrobial peptides. Their pharmacological properties include an unusually broad spectrum of antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi and some enveloped viruses. Preclinical and clinical studies of the lead compound, IB-367, developed for topical applications, show promise for the prevention of chemotherapy- and radiation-induced oral mucositis.     

Protegrins: new antibiotics of mammalian origin

Protegrins and their derivatives are a new class of peptide antibiotics based on mammalian antimicrobial peptides. Their pharmacological properties include an unusually broad spectrum of antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi and some enveloped viruses. Preclinical and clinical studies of the lead compound, IB-367, developed for topical applications, show promise for the prevention of chemotherapy- and radiation-induced oral mucositis.     

On the origin of antibiotics and mycotoxins

Antibiotics and mycotoxins share many remarkable similarities in structure, metabolic roles and biosynthesis, indicating their differences are primarily in the minds and economies of man, not the perspectives of producing organisms. Antibiotic/mycotoxin biosynthetic gene packages appear to have been assembled by transposon-mediated processes combining genes acquired horizontally from plants and other soil microbes with genes from the producing organism’s own genome. Probable gene sources include those for the synthesis and secretion of plant phytoalexins, toxins, allelochemicals, pheromones, germination inhibitors and pigments, and bacterial quorum-sensors and siderophores. Understanding antibiotic origins may assist in the discovery and creation of new antibiotics.     

Cephabacin M1-6, new 7-methoxycephem antibiotics of bacterial origin. I. A producing organism, fermentation, biological activities, and mode of action

New 7-methoxycephem antibiotics were found in culture filtrates of a bacterium isolated from a plant and named cephabacin M1-6. They are the first members of 7-methoxycephem antibiotics of bacterial origin. The producing organism was taxonomically characterized and identified as Xanthomonas lactamgena YK-431; other strains of this species have recently been reported to produce cephabacin F and H group antibiotics. Cephabacin M1-6 exhibited moderate antibacterial activity against Gram-negative and Gram-positive bacteria. Cephabacin M1-6 were as stable as cephamycin C to cephalosporinases. They showed inhibitory activity against a cephalosporinase of Proteus vulgaris GN 4413. The mode of action of cephabacin M1 was examined using Escherichia coli and Bacillus subtilis as test organisms; primary lethal targets of cephabacin M1 are penicillin-binding protein (PBP) 1 in E. coli and PBP 4 in B. subtilis.     

新型糖肽类抗生素B7011对细菌感染小鼠败血症的体内抗菌作用研究

目的 评价新型糖肽类抗生素B7011对临床分离致病菌所致小鼠败血症的体内抗菌作用。方法 以耐万古霉素屎肠球菌(vanomycin-resistant Enterococci, VRE)、甲氧西林敏感金葡球菌(methicillin sensitive Staphylococcus aureus, MSSA)和耐甲氧西林金黄色葡萄球菌(methicillin resistant Staphylococcus aureus, MRSA)感染败血症小鼠为动物模型，经尾静脉注射B7011及万古霉素，比较两药对感染小鼠的保护作用。结果 B7011对MSSA、MRSA、VRE感染小鼠败血症模型有明显保护作用。其ED50分别为0.722、0.193和0.395mg/kg。与万古霉素比较，在MRSA和VRE感染的小鼠败血症模型保护试验中，两药的ED50参数比较P<0.05，有显著差异；在对MSSA感染的小鼠败血症模型保护模型中，两药的ED50参数比较P>0.05，无显著差异。结论 实验结果表明，B7011对革兰阳性菌有很好的抗菌作用，尤其是可以显著降低耐药菌急性感染败血症小鼠的死亡数量，其保护作用明显优于万古霉素。结合体外试验结果，说明B7011有望成为临床上应用于耐药菌感染的，具有较好疗效的新型抗生素。     

Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature

By screening cultures of soil bacteria, we re-discovered an old antibiotic (nybomycin) as an antibiotic with a novel feature. Nybomycin is active against quinolone-resistant Staphylococcus aureus strains with mutated gyrA genes but not against those with intact gyrA genes against which quinolone antibiotics are effective. Nybomycin-resistant mutant strains were generated from a quinolone-resistant, nybomycin-susceptible, vancomycin-intermediate S. aureus (VISA) strain Mu 50. The mutants, occurring at an extremely low rate (<1 × 10(-11)/generation), were found to have their gyrA genes back-mutated and to have lost quinolone resistance. Here we describe nybomycin as the first member of a novel class of antibiotics designated 'reverse antibiotics'.     

Calcium-dependent anticandidal action of pradimicin A

Pradimicin A shows candicidal activity at 10 micrograms/ml in vitro. The action of pradimicin A on Candida albicans cells involves a set of specific cell surface interactions in a Ca2(+)-dependent manner. These include binding to the mannan components on the cell surface and subsequent interactions at the level of the plasma membrane, causing K+ leakage and cell death. The protoplasts prepared from C. albicans undergo lysis rapidly when treated with pradimicin A. These results suggest that pradimicin A acts primarily on the candidal plasma membrane, leading to a perturbation of membrane function.     

New antibiotics for severe ICU-aquired bacterial infections

Infection is a major cause of morbidity and mortality in intensive care units (ICU). The impact on prognostic of an inadequate antibiotic therapy is well established. The problem is due to the growing spread of resistant microorganisms, including both Gram-negative and Gram-positive pathogens, especially in the case of ICU-acquired infections. In this context, antibiotics with broad spectrum activity are usually required. Moreover, these antibiotics should reach high concentrations in tissues, especially in lungs, and should exert a bactericidal activity for the most severely ill patients, especially those with bloodstream infections. A frequent problem in clinical practice is the lack of data validating their use in the context of critically ill patients. In the present article, we review the newest antibiotics that could be of interest for severe ICU-acquired infections: tigecycline, moxifloxacine, the newer carbapenems, linezolide and daptomycine. We discuss their approved indications and identify the fields in which they could be used to treat infections acquired in the ICU.     

Monitoring bacterial resistance to restricted antibiotics.

Data on patterns of resistance of eight strains of bacteria toward various restricted antibiotics were collected from 18 public health laboratories in Czechoslovakia. Development of bacterial resistance to gentamicin and colistin did not appear to follow the resistance patterns of bacteria toward more commonly used antibiotics, but there did appear to be a tendency of mutual coresistance to those two drugs in E. coli and Pseudomonas strains. Similarly, oxacillin coresistance was found in lincomycin-resistant staphylococcal strains. Computer-assisted analysis of resistant bacterial strains revealed otherwise-hidden tendencies and mutual relationships among drugs newly marketed in Czechoslovakia.