In Vitro Studies of a New Semisynthetic Penicillin, 6-(D-α-Sulfoaminophenylacetamido)-Penicillanic Acid

The activity of 6-(D-α-sulfoaminophenylacetamido)-penicillanic acid was determined against 357 clinical isolates of gram-negative bacilli by use of the tube-dilution technique. The majority of the isolates of Pseudomonas species were inhibited by 200 μg/ml or less of this antibiotic. Most of the isolates of Escherichia coli had a minimal inhibitory concentration of 50 μg/ml or less. Seventy-three per cent of the isolates of P. mirabilis, 40% of the isolates of P. morganii, and 45% of the isolates of Enterobacter species were inhibited by 12.5 μg/ml or less, whereas most of the isolates of Klebsiella species and Serratia species were resistant. The activity of this semisynthetic penicillin was affected by the size of the inoculum. The drug was bactericidal against all isolates of E. coli and Proteus species that were sensitive to it, but it was bactericidal against only 32% of the sensitive isolates of Pseudomonas species.     

In Vitro Studies of α-Carboxyl-3-Thienylmethyl Penicillin,a New Semisynthetic Penicillin

The activity of a new semisynthetic penicillin, α-carboxyl-3-thienylmethyl penicillin (BRL-2288) was determined against 535 clinical isolates of gram-negative bacilli, by using the tube dilution technique. Nearly 80% of isolates of Proteus spp. were inhibited by 3.12 μg or less of this antibiotic per ml. BRL-2288 was as active as ampicillin against Escherichia coli. It was slightly more active than carbenicillin or 6-(d-α-sulfoaminophenylacetamido)-penicillanic acid against Pseudomonas sp., with over half of the isolates being inhibited by 50 μg or less of BRL-2288 per ml. Isolates of Klebsiella sp. were routinely resistant to this antibiotic. The drug was bactericidal against most sensitive organisms. BRL-2288 was less active against large inocula. A strain of Pseudomonas sp. which developed resistance to carbenicillin also developed resistance to BRL-2288 simultaneously.     

In Vitro Antimicrobial Activity and Human Pharmacology of Cephalexin, a New Orally Absorbed Cephalosporin C Antibiotic

Concentrations of cephalexin (an orally absorbed derivative of cephalosporin C) in serum and urine were determined in normal volunteers and patients. The in vitro antibacterial activity was also studied. All strains of group A β-hemolytic streptococci and Diplococcus pneumoniae were inhibited by 3.1 μg/ml. Of the Staphylococcus aureus strains, 88% were inhibited by 6.3 μg/ml, and 12.5 μg/ml was inhibitory for all S. aureus, 80% of Escherichia coli, 72% of Klebsiella-Aerobacter, and 56% of Proteus mirabilis strains. About 90 to 96% of E. coli, Klebsiella Aerobacter, and P. mirabilis strains were inhibited by 25 μg of cephalexin per ml. Pseudomonas and indole-positive Proteus strains proved to be quite resistant to cephalexin. Cephalexin was well absorbed after oral administration. A peak serum concentration of cephalexin of at least 5 μg/ml was achieved in each volunteer with 250 and 500-mg doses. A mean peak serum concentration of 7.7 μg/ml was achieved with 250-mg doses; 12.3μg/ml was achieved with 500-mg doses of antibiotic. Food did not interfere with absorption. Probenecid enhanced both the peak serum concentration and the duration of antibiotic activity in the serum. Over 90% of the administered dose was excreted in the urine within 6 hr. The mean peak serum concentration of cephalexin after an oral dose of 500 mg was adequate to inhibit all group A streptococci, D. pneumoniae, and S. aureus, 85% of E. coli, and about 40 to 75% of Klebsiella-Aerobacter and P. mirabilis strains. Levels of cephalexin in urine were adequate to inhibit over 90% of E. coli, and P. mirabilis and 80 to 96% of Klebsiella-Aerobacter strains.     

A new method of preparation of pyocyanin and demonstration of an unusual bacterial sensitivity.

Pyocyanin was prepared in 60% yield from phenazine methoxysulfate by a photooxidation procedure and purification by silica gel chromatography. Monitoring was performed by thin-layer chromatography. Approximately 50% of clinical Pseudomonas aeruginosa isolates were found to produce pyocyanin at 37°C. Among Proteus strains, P. morganii strains were sensitive to concentrations of pyocyanin 16 to 64 times lower than concentrations that inhibited the growth of P. mirabilis and P. vulgaris strains.     

Klebsiella, Enterobacter, and Serratia: Biochemical Differentiation and Susceptibility to Ampicillin and Three Cephalosporin Derivatives

Three hundred twenty-nine strains of the tribe Klebsielleae were compared by several biochemical tests and by susceptibility to selected antibiotics. Biochemical tests included urease, amino acid decarboxylase, and hydrogen sulfide production; fermentation of lactose and dextrose; motility; and tests in the IMViC (indole, methyl red, Voges-Proskauer, citrate) series. The isolates were: Klebsiella species, 67.5%; Enterobacter species, 28%, and Serratia species, 4.5%. Minimal inhibitory concentrations of cephaloridine, cephalothin, and a new cephalosporin, cephalexin, and of ampicillin were determined by the agar dilution procedure. Cephalosporins at 20 mug/ml or less inhibited 90% of the Klebsiella strains but only 15% of the Enterobacter strains. Ampicillin inhibited 27% of Enterobacter strains and 17% of Klebsiella strains. Serratia isolates were insensitive to the cephalosporins and ampicillin. The results suggest that precise identification of this group to the generic level can be accomplished readily in the clinical laboratory and that such information is helpful in the preliminary selection of an antibiotic for treatment of clinical infections.     

Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part I: Aspidosperma nitidum (Benth) used as a remedy to treat fever and malaria in the Amazon

Infusions of Aspidosperma nitidum (Apocynaceae) wood bark are used to treat fever and malaria in the Amazon Region. Several species of this family are known to possess indole alkaloids and other classes of secondary metabolites, whereas terpenoids, an inositol and the indole alkaloids harmane-3 acid and braznitidumine have been described in A. nitidum . In the present study, extracts from the wood bark, leaves and branches of this species were prepared for assays against malaria parasites and cytotoxicity testing using human hepatoma and normal monkey kidney cells. The wood bark extracts were active against Plasmodium falciparum and showed a low cytotoxicity in vitro, whereas the leaf and branch extracts and the pure alkaloid braznitidumine were inactive. A crude methanol extract was subjected to acid-base fractionation aimed at obtaining alkaloid-rich fractions, which were active at low concentrations against P. falciparum and in mice infected with and sensitive Plasmodium berghei parasites. Our data validate the antimalarial usefulness of A. nitidum wood bark, a remedy that can most likely help to control malaria. However, the molecules responsible for this antimalarial activity have not yet been identified. Considering their high selectivity index, the alkaloid-rich fractions from the plant bark might be useful in the development of new antimalarials.     

Selection and characterization of mexican strains ofBacillus thuringiensis active against four major lepidopteran maize pests

In order to isolate novel delta-endotoxins fromBacillus thuringiensis Berliner, a total of 426 native isolates (in varying numbers for each pest) were screened against four major maize pests: corn earworm,Helicoverpa zea; fall armyworm,Spodoptera frugiperda; southwestern corn borer,Diatraea graridiosella, and sugarcane borer,Diatraea saccharalis. Spore-crystal complexes from the isolates were integrated into semi-artificial diets of each pest and mortality was assessed 7 days after treatment. A total of 25 isolates were selected on the basis of highest larval mortality against at least one insect species. There was no correspondence of the most toxic isolates when tested against the four different insect species. Most of the 25 selected isolates caused higher toxicities against all four pests than the standard strain HD-1, regardless of not achieving 100% mortality in any bioassay.H. zea demonstrated the highest level of mortality (96%) and was susceptible to the largest number of isolates (98). None of the other insect species were found susceptible at levels greater than 60%. All the selected active strains were isolated from stored grain dusts (except for LBIT-167), and had bipyramidal crystals with Cry I-like proteins. Most isolates also formed an associated square (cubic) inclusion, with Cry Il-like proteins according to SDS-PAGE analysis of their parasporal bodies. The most active isolates will be subjected to further studies, in order to identify putative novel genes to be expressed in transgenic maize     

1-N-(S-3-amino-2-hydroxypropionyl) gentamicin B (Sch 21420): A collaborative in vitro susceptibility comparison with amikacin and gentamicin against 12,984 clinical bacterial isolates

Schering Compound Sch 21420 is an aminoglycoside with antibacterial activity similar to amikacin but with a potential for renal toxicity lower than that of gentamicin. The in vitro activity of Sch 21420, amikacin, and gentamicin was compared with 12,984 bacterial isolates from six clinical laboratories. Agar dilution and broth microdilution techniques were both used with comparable results. Against most of the Enterobacteriaceae, Sch 21420 had equal or only slightly greater activity than amikacin.Proteus species were generally more susceptible to amikacin and gentamicin. Gentamicin was more active against most isolates included in this study.Pseudomonas aeruginosa recovered in the different institutions showed marked variations in susceptibility to gentamicin; amikacin and Sch 21420 were effective against most gentamicin-resistant strains that produce inactivating enzymes: but all three drugs were ineffective against permeability mutants. If diminished renal- and ototoxicity are confirmed, Sch 21420 promises to be a welcome addition to the antibiotic armamentarium.     

Drug Resistance of Enteric Bacteria IX. Distribution of R Factors in Gram-negative Bacteria from Clinical Sources

Many isolates belonging to the Enterobacteriaceae were collected in 1965 from the inpatients at geographically scattered hospitals in Japan. Among 2,650 Shigella strains examined, 58.4% were found to be drug-resistant; 95.0% of these resistant strains were multiply resistant. Among 434 resistant strains examined, 81% carried R factors that were transferable by cell-to-cell contact. Of 160 isolates of other enteric bacteria, drug-resistant strains included 84.2% of the Escherichia coli, 93.0% of the Klebsiella, and 90.0% of the Proteus cultures. Among these resistant strains, 70.3% of the E. coli, 66.7% of the Klebsiella, and 52.0% of the Proteus were multiply resistant. Of these resistant strains, 84.0% of the E. coli, 88.0% of the Klebsiella, and 50.0% of the Proteus strains carried R factors. These results indicate that R factors are widespread among gram-negative bacteria of clinical significance.     

Molecular and Genetic Analyses of the Putative Proteus O Antigen Gene Locus

Proteus species are well-characterized opportunistic pathogens primarily associated with urinary tract infections (UTI) of humans. The Proteus O antigen is one of the most variable constituents of the cell surface, and O antigen heterogeneity is used for serological classification of Proteus isolates. Even though most Proteus O antigen structures have been identified, the O antigen locus has not been well characterized. In this study, we identified the putative Proteus O antigen locus and demonstrated this region''s high degree of heterogeneity by comparing sequences of 40 Proteus isolates using PCR-restriction fragment length polymorphism (RFLP). This analysis identified five putative Proteus O antigen gene clusters, and the probable functions of these O antigen-related genes were proposed, based on their similarity to genes in the available databases. Finally, Proteus-specific genes from these five serogroups were identified by screening 79 strains belonging to the 68 Proteus O antigen serogroups. To our knowledge, this is the first molecular characterization of the putative Proteus O antigen locus, and we describe a novel molecular classification method for the identification of different Proteus serogroups.Proteus species are usually found in soil, water, and sewage and are well-known opportunistic pathogens that most commonly cause urinary tract infections (UTIs) in persons with anatomical and physiological defects of their urinary tracts (15, 28). This genus includes the five named species P. mirabilis, P. vulgaris, P. myxofaciens, P. penneri, and P. hauseri and the three unnamed Proteus genomospecies 4, 5, and 6 (20, 21). Among these, P. mirabilis, P. vulgaris, and P. penneri are the most common human pathogens (28). Among Proteus species, P. mirabilis is most frequently associated with UTIs and is a common cause of catheter-associated UTIs (12).Potential virulence factors and bacterial behaviors associated with the infection processes and disease, including swarming, growth rates, fimbria expression, flagella, and the production of hemolysins, ureases, proteases, and amino acid deaminases, in addition to the expression of lipopolysaccharide (LPS) antigens and capsular polysaccharides (CPSs), have been described in many studies (11, 18, 28). Both LPSs and CPSs have been considered to play an important role in the progression of UTIs, in addition to affecting both kidney and bladder stone formation (7, 25, 35). Furthermore, the LPS O antigen confers protection against serum-mediated bactericidal activity (13, 27), and bacterial LPS released from bacteria is a biologically active endotoxin that causes a broad spectrum of pathophysiological conditions, including septic shock (26). Recently, two additional virulence factors with cytotoxic and agglutination properties, the high-affinity phosphate transporter (Pst) and the autotransporter (Pta), have been described (1, 11).The O antigen located on the cell surface of Gram-negative bacteria consists of oligosaccharide repeats (O unit) that normally contain 2 to 8 sugar residues. The O antigen is one of the most variable constituents on the cell surface, due to variations in the types of sugars present and their arrangements and respective linkages, and is subject to intense selection by the host immune system and bacteriophages. The serological classification scheme established by Kauffman and Perch defines 49 different P. mirabilis and P. vulgaris O serogroups (10), and an additional 11 serogroups were later proposed (23). In the case of P. penneri, an additional 15 O antigen serogroups were described (16, 42; Z. Sidorczyk, K. Zych, K. Kolodziejska, D. Drzewiecka, and A. Zablotni, presented at the Second German-Polish-Russian Meeting on Bacterial Carbohydrates, Moscow, Russia, 10 to 12 September 2002). To date, the O antigen structures of 78 Proteus species have been described (unpublished data), and uronic acid, which can sometimes be substituted for amino acids, was identified as a component of the Proteus O antigen. Although acidic O-specific polysaccharides have been identified in most Proteus O antigens, a study of the genetic locus associated with Proteus O antigens has never been carried out.The genome sequence of P. mirabilis was published for the first time in 2008 (22). In this study, we characterized the putative O antigen locus by analyzing genomic sequences and confirming the locus heterogeneity by carrying out PCR-restriction fragment length polymorphism (RFLP) on 40 strains. Four putative O antigen gene clusters were sequenced and analyzed, and specific primers were identified for Proteus species by screening 79 Proteus strains, confirming that the identified loci were specific to particular serogroups.     

Cefaclor uptake by the proton-dependent dipeptide transport carrier of human intestinal Caco-2 cells and comparison to cephalexin uptake.

The human Caco-2 cell line spontaneously differentiates in culture to epithelial cells possessing intestinal enterocytic-like properties. These cells possess a proton-dependent dipeptide transport carrier that mediates the uptake of the cephalosporin antibiotic cephalexin (Dantzig, A.H. and Bergin, L. (1990) Biochim. Biophys. Acta 1027, 211-217). In the present study, the uptake of cefaclor was examined and found to be sodium-independent, proton-dependent, and energy-dependent. The initial rate of D-[3-phenyl-3H]cefaclor uptake was measured over a wide concentration range; uptake was mediated by a single saturable transport carrier with a Km of 7.6 mM and a Vmax of 7.6 nmol/min per mg protein and by a non-saturable component. Uptake was inhibited by dipeptides but not amino acids. The carrier showed a preference for the L-isomer. The effect of the presence of a 5-fold excess of other beta-lactam antibiotics was examined on the initial rates of 1 mM cefaclor and 1 mM cephalexin uptake. Uptake rates were inhibited by the orally absorbed antibiotics, cefadroxil, cefaclor, loracarbef, and cephradine and less so by the parenteral agents tested. The initial uptake rates of both D-[9-14C]cephalexin and D-[3-phenyl-3H]cefaclor were competitively inhibited by cephalexin, cefaclor, and loracarbef with Ki values of 9.2-13.2, 10.7-6.2, and 7.7-6.4 mM, respectively. Taken together, these data suggest that a single proton-dependent dipeptide transport carrier mediates the uptake of these orally absorbed antibiotics into Caco-2 cells, and provide further support for the use of Caco-2 cells as a cellular model for the study of the intestinal proton-dependent dipeptide transporter.     

Quantitative detection of Proteus species by real-time polymerase chain reaction using SYBR Green I

A SYBR Green real-time polymerase chain reaction (PCR) method for rapid detection of Proteus species was developed and evaluated. Of 322 clinical and food samples tested, 75 samples were positive for Proteus species by using conventional PCR and real-time PCR assays. The results were consistent with standard culture methods and the Vitek auto-microbe system, indicating a 100 % specificity obtained by both PCR assays. For the real-time PCR method, the minimum detectable level was 10 colony forming units (CFU) /ml, which was a 10³ multiple higher than the conventional PCR method. Correlation coefficients of standard curves which were constructed using the threshold cycle (Ct) versus copy numbers of Proteus showed good linearity (R ²?=?0.997). In conclusion, several significant advantages such as higher sensitivity and rapidness were observed by using the SYBR Green real-time PCR method for identifying Proteus species.     

The antimicrobial activity of lapachol and its thiosemicarbazone and semicarbazone derivatives

Lapachol was chemically modified to obtain its thiosemicarbazone and semicarbazone derivatives. These compounds were tested for antimicrobial activity against several bacteria and fungi by the broth microdilution method. The thiosemicarbazone and semicarbazone derivatives of lapachol exhibited antimicrobial activity against the bacteria Enterococcus faecalis and Staphylococcus aureus with minimal inhibitory concentrations (MICs) of 0.05 and 0.10 µmol/mL, respectively. The thiosemicarbazone and semicarbazone derivatives were also active against the pathogenic yeast Cryptococcus gattii (MICs of 0.10 and 0.20 µmol/mL, respectively). In addition, the lapachol thiosemicarbazone derivative was active against 11 clinical isolates of Paracoccidioides brasiliensis, with MICs ranging from 0.01-0.10 µmol/mL. The lapachol-derived thiosemicarbazone was not cytotoxic to normal cells at the concentrations that were active against fungi and bacteria. We synthesised, for the first time, thiosemicarbazone and semicarbazone derivatives of lapachol. The MICs for the lapachol-derived thiosemicarbazone against S. aureus, E. faecalis, C. gattii and several isolates of P. brasiliensis indicated that this compound has the potential to be developed into novel drugs to treat infections caused these microbes.     

A Brevibacillus sp. antagonistic to mycotoxigenic Fusarium spp.

Antagonistic microbes were isolated from soils to control mycotoxin contamination of cereals by limiting the growth of mycotoxigenic Fusarium species. In total, 341 bacterial isolates were examined for antifungal activity against eight mycotoxigenic Fusarium species using dual culture assays. The screening identified 11 isolates that inhibited mycelial growth of all Fusarium species tested. The culture filtrates of 2 of the 11 isolates completely inhibited germination of conidia up to 21 days of incubation. These two isolates exhibited identical activity toward the fungi tested and were identified as Brevibacillus spp. based on 16S rRNA sequence homology. The most closely related species based on phylogenetic analysis was Brevibacillus reuszeri. Additional dual culturing using further fungal species showed that the antagonistic Brevibacillus inhibited the growth of most Fusarium species tested (39 of 46 species), two Epicoccum spp., one Alternaria sp., three Aspergillus spp. (3 of 11), and three Penicillium spp. (3 of 8). The in vivo assay was performed to test the efficacy of antagonistic Brevibacillus isolates on maize ears and revealed that the application of microbes suppressed ear rot (ANOVA, p = 0.0020). This Brevibacillus sp. may be an antagonist of the majority of Fusarium species, including mycotoxigenic species.     

Susceptibility of Neisseria gonorrhoeae to seven antibiotics in vitro

One hundred consecutive isolates of N. gonorrhoeae were tested for susceptibility to penicillin, ampicillin, tetracycline, erythromycin, kanamycin, cephaloridine and cephalexin by an agar dilution method. Relative resistance to penicillin was frequent. For 39% of isolates the minimum inhibitory concentration (MIC) of penicillin was 0.05 U./ml. or less; in 55% the MIC was 0.5 to 2.0 U./ml. Ampicillin was slightly more active than penicillin G: all isolates were inhibited by 0.5μg./ml. or less. Resistance to tetracycline and erythromycin was frequent with MIC of 1 μg./ml. or greater observed in 32 and 24% of isolates respectively. The MIC of kanamycin for all gonococci was 8 μg./ml. or greater. Cephalexin was slightly more active than cephaloridine, though each drug exhibited a wide range of MIC values. Gonococcus isolates resistant to penicillin (MIC of 1.0 U./ml. or greater) tended to be resistant to the other antibiotics tested.     

Characterization of Burkholderia cepacia complex from cystic fibrosis patients in China and their chitosan susceptibility

A survey of Burkholderia cepacia complex (Bcc) species was conducted in sputum from cystic fibrosis (CF) patients in China. One hundred and four bacterial isolates were recovered on B. cepacia selective agar and 42 of them were assigned to Bcc by PCR assays. The species composition of the Bcc isolates from CF sputum was analyzed by a combination of recA-restriction fragment length polymorphism assays, species-specific PCR tests and recA gene sequencing. The results revealed that the 42 Bcc isolates belong to B. cepacia, B. cenocepacia and B. contaminans while predominant Bcc species was B. cenocepacia. This is the first report of B. contaminans from CF sputum in China. In addition, results from this study showed that chitosan solution at 10, 25, 50 and 100 μg/ml markedly inhibited the growth of the 16 representative isolates from the three different Bcc species, which indicated that chitosan was a potential bactericide against Bcc bacteria.     

Identification and nematicidal activity of bacteria isolated from cow dung

Two hundred and nineteen bacterial strains were isolated from cow dung. Among these, 59 isolates displayed nematicidal activity against the model nematode Caenorhabditis elegans. Of the 59 bacterial strains, 17 killed >90 % of the tested nematodes within 1 h. Based on their 16S rRNA sequences, these 17 strains were identified as Alcaligenes faecalis, Bacillus cereus, Proteus penneri, Providencia rettgeri, Pseudomonas aeruginosa, Pseudomonas otitidis, Staphylococcus sciuri, Staphylococcus xylosus, Microbacterium aerolatum, Pseudomonas beteli. Among these 17 strains, 14 produced volatile organic compound(s) that inhibited the mobility of the C. elegans nematodes. These 14 strains also showed nematicidal activity against a plant pathogenic nematode Meloidogyne incognita. This is the first report demonstrating nematicidal activity for strains in genera Proteus, Providencia and Staphylococcus.     

Exploring the therapeutic potential of Hibiscus rosa sinensis synthesized cobalt oxide (Co3O4-NPs) and magnesium oxide nanoparticles (MgO-NPs)

Herein, we present a green, economic and ecofriendly protocol for synthesis of cobalt oxide (Co₃O₄-NPs) and magnesium oxide nanoparticles (MgO-NPs) for multifaceted biomedical applications. In the study, a simple aqueous leaf extract of Hibiscus rosa sinensis, was employed for the facile one pot synthesis of Co₃O₄-NPs and MgO-NPs. The well characterized NPs were explored for multiple biomedical applications including bactericidal activity against urinary tract infection (UTI) isolates, leishmaniasis, larvicidal, antidiabetic antioxidant and biocompatibility studies. Our results showed that both the NPs were highly active against multidrug resistant UTI isolates as compared to traditional antibiotics and induced significant zone of inhibition against Proteus Vulgaris, Pseudomonas Aurigenosa and E.coli. The NPs, in particular Co₃O₄-NPs also showed significant larvicidal activity against the Aedes Aegypti, the mosquitoes involve in the transmission of Dengue fever. Similarly, excellent leishmanicidal activity was also observed against both the promastigote and amastigote forms of the parasite. Furthermore, the particles also exhibited considerable antidiabetic activity by inhibiting α-amylase and α-glucosidase enzymes. The biosynthesized NPs were found to be excellent antioxidant and biocompatible nanomaterials. Owing to ecofriendly synthesis, non-toxic and biocompatible nature, the Hibiscus rosa sinensis synthesized Co₃O₄-NPs and MgO-NPs can be exploited as potential candidates for multiple biomedical applications.     

Cephalexin and Cephaloglycin Activity In Vitro and Absorption and Urinary Excretion of Single Oral Doses in Normal Young Adults

A large number of recently isolated bacterial pathogens were tested for susceptibility to cephalexin and cephaloglycin by the replica inoculating method. Strains of group A hemolytic streptococci, viridans (alpha and gamma) streptococci, pneumococci, gonococci, meningococci, and penicillin G-sensitive Staphylococcus aureus were all moderately to highly susceptible to both of these cephalosporin analogues, nearly all of the strains being two to eight (median four) times more susceptible to cephaloglycin than to cephalexin. The penicillin G-resistant, penicillinase-producing strains of S. aureus varied in their susceptibility; many were moderately resistant to both analogues, particularly to cephalexin. Strains of enterococci, Haemophilus influenzae, and most of the common gram-negative bacilli were moderately to highly resistant. Reducing the size of the inoculum had variable effects on inhibition by these drugs, depending on the species or strain. The activity of cephalexin was very little affected by pH of the medium within the clinical range or by incubation at 37 C in broth for up to 24 hr. In contrast, cephaloglycin in broth deteriorated rapidly at 37 C, and its activity was markedly reduced in alkaline medium. Both cephalexin and cephaloglycin were rapidly absorbed and excreted into the urine after single oral doses of 500 mg. Much higher levels were achieved and sustained with the former. Absorption of both analogues was delayed when taken with food, and the levels in the serum were significantly higher and better sustained when probenecid was also given. Very high concentrations of cephalexin were excreted into the urine during the first 4 hr, and the levels were still high in the 4- to 8-hr collection. The concentrations of cephaloglycin in the urine at these times were much lower. An average of 80 to 93% of the dose of cephalexin and 25 to 30% of the cephaloglycin were accounted for as active drug in the urine collected in 8 hr. Both analogues were well tolerated.     

New β-lactam – Tetramic acid hybrids show promising antibacterial activities

β-Lactams are the most important class of antibiotics, for which the emergence of resistance threatens their utility. As such, we explored the extent to which the tetramic acid motif, frequently found in naturally occurring antibiotics, can be used to generate novel β-lactam antibiotics with improved antibacterial activity. We synthesized new ampicillin – tetramic acid, cephalosporin – tetramic acid, and cephamycin – tetramic acid analogs and evaluated their activities against problematic Gram-positive and Gram-negative pathogens. Amongst the analogs, a 7-aminocephalosporanic acid analog, 3397, and a 7-amino-3-vinyl cephalosporanic acid, 3436, showed potent activities against S. aureus NRS 70 (MRSA) with MICs of 6.25?μg/mL and 3.13?μg/mL respectively. These new analogs were ≥16-fold more potent than cefaclor and cephalexin. Additionally, a Δ² cephamycin – tetramic acid analog 3474 which contained a basic guanidinium substituent at the 5-position of the tetramic acid core displayed potent activity against several clinical strains of K. pneumoniae and E. coli.