Gram-negative Activity Research Articles

Avoidable Antibiotic Exposure for Uncomplicated Skin and Soft Tissue Infections in the Ambulatory Care Setting

BackgroundUncomplicated skin and soft tissue infections are among the most frequent indications for outpatient antibiotics. A detailed understanding of current prescribing practices is necessary to optimize antibiotic use for these conditions. MethodsThis was a retrospective cohort study of children and adults treated in the ambulatory care setting for uncomplicated cellulitis, wound infection, or cutaneous abscess between March 1, 2010 and February 28, 2011. We assessed the frequency of avoidable antibiotic exposure, defined as the use of antibiotics with broad gram-negative activity, combination antibiotic therapy, or treatment for 10 or more days. Total antibiotic-days prescribed for the cohort were compared with antibiotic-days in 4 hypothetical short-course (5-7 days), single-antibiotic treatment models consistent with national guidelines. ResultsA total of 364 cases were included for analysis (155 cellulitis, 41 wound infection, and 168 abscess). Antibiotics active against methicillin-resistant Staphylococcus aureus were prescribed in 61% of cases of cellulitis. Of 139 cases of abscess where drainage was performed, antibiotics were prescribed in 80% for a median of 10 (interquartile range, 7-10) days. Of 292 total cases where complete prescribing data were available, avoidable antibiotic exposure occurred in 46%. This included use of antibiotics with broad gram-negative activity in 4%, combination therapy in 12%, and treatment for 10 or more days in 42%. Use of the short-course, single-antibiotic treatment strategies would have reduced prescribed antibiotic-days by 19% to 55%. ConclusionsApproximately half of uncomplicated skin infections involved avoidable antibiotic exposure. Antibiotic use could be reduced through treatment approaches using short courses of a single antibiotic.

Prevalence and Antimicrobial Susceptibility Pattern of Extended Spectrum Beta Lactamase (ESBL) and non-ESBL Producing Enteric Gram-Negative Bacteria and Activity of Nitrofurantoin in the era of ESBL

Background: Resistance in enteric Gram-negative bacteria is of a great concern and concise local data are lacking. Objectives: To determine prevalence and antimicrobial susceptibility pattern of Extended Spectrum Beta-Lactamase (ESBL) and non-ESBL producing enteric Gram-negative bacteria. Materials and Methods: In a descriptive study in Tehran, patients’ samples have been obtained and were inoculated on blood and MacConkey agar plates at microbiology laboratory hospital, and a total of 292 Gram-negative species were isolated at Microbiology Laboratory from patients’ specimens. Susceptibility pattern was determined by disk diffusion method based on Kirby-Bauer method on Mueller-Hinton agar plate. SPSS 16 software (descriptive analysis, Chi-square) was used for statistical analysis of this study. Results: Escherichia coli was the most common organism [189 (64.7%)], followed by Acinetobacter baumannii [40 (13.7%)], Pseudomonas aeruginosa [32 (11%)], Klebsiella pneumoniae [26 (8.9%)], Proteus mirabilis [4 (1.4%)], and Serratia marcescense [1 (0.3%)]. 122 (41.8%) of isolates were classified as ESBL - producers. E. coli accounted for most of the ESBL-producer bacteria, followed by K. pneumoniae. 170 (58.2%) of isolates were non-ESBL producers. All of the ESBL producer isolates were sensitive to imipenem, piperacillin-tazobactam and colistin whereas resistance to these antibiotics in the non-ESBL group was seen. The rate of resistance to nitrofurantoin in ESBL group was lower than of that in non-ESBL group. The majority of the ESBL isolates of resistant to trimethoprim-sulfamethoxazole, ciprofloxacin, the third generation cephalosprins (ceftriaxone, cefixime, and cefotaxime), gentamicin and amikacin, were sensitive to nitrofurantoin. Conclusion: Although all ESBL producer Gram-negative bacteria were sensitive to imipenem, piperacillin-tazobactam, and colistin, non-ESBL isolates showed resistant pattern. Interestingly, notable percent of mentioned resistant isolates were sensitive to nitrofurantoin.

Design, synthesis, and in vitro antibacterial screening of some novel 3-pentyloxy-1-hydroxyxanthone derivatives

A series of 3-pentyloxy-1-hydroxyxanthone derivatives were synthesized by four-step reactions: first cyclocondensation between salicylic acid and phloroglucinol in the presence of Eaton’s reagents, then alkylation with 1,5-dibromopentane, followed by nucleophilic substitution by different nucleophiles to obtain final compounds. Molecular structures of the synthesized compounds were elucidated by FT-IR, 1H NMR, 13C NMR, mass spectral data, and elemental analysis. The in vitro antibacterial activity was evaluated by MIC determination using broth dilution method against representative three Gram-positive and three Gram-negative bacterial strains with reference to ofloxacin. All the synthesized compounds showed antibacterial activity; besides the compounds 7f and 7g showed better Gram-positive and Gram-negative antibacterial activities.

Role of Amphiphilicity in the Design of Synthetic Mimics of Antimicrobial Peptides with Gram-Negative Activity

Two new series of aryl SMAMPs (synthetic mimics of antimicrobial peptides) with facially amphiphilic (FA) and disrupted amphiphilic (DA) topologies were designed and synthesized to directly assess the role of amphiphilicity on their antimicrobial activity against gram-positive and gram-negative bacteria in closely related structures. The FA SMAMPs displayed broad spectrum antimicrobial activity against both gram-positive S. aureus and gram-negative E. coli, whereas the DA SMAMPs, which contained a polar amide bond in between the hydrophobic moieties, only exhibited activity towards S. aureus with increasing hydrophobicity. The integy moment (IW) was used to quantify the amphiphilicity of the SMAMPs and confirmed that it is critical for the design of SMAMPs with gram-negative activity.

Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II: Development of inhibitors with broad spectrum, Gram-negative antibacterial activity

The structurally related bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as prime candidates for the development of broad spectrum antibacterial agents. However, GyrB/ParE targeting antibacterials with spectrum that encompasses robust Gram-negative pathogens have not yet been reported. Using structure-based inhibitor design, we optimized a novel pyrrolopyrimidine inhibitor series with potent, dual targeting activity against GyrB and ParE. Compounds were discovered with broad antibacterial spectrum, including activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli. Herein we describe the SAR of the pyrrolopyrimidine series as it relates to key structural and electronic features necessary for Gram-negative antibacterial activity.

Contribution of Structural Domains to the Activity of Ribonuclease 7 against Uropathogenic Bacteria

Ribonuclease 7 (RNase 7) is a 14.5-kDa peptide that possesses potent antimicrobial properties against Gram-negative and Gram-positive bacteria and is expressed in a variety of epithelial tissues. Little is known about its mechanisms of action and the determinants of its antimicrobial properties. The objective of this study was to identify the intrinsic functional domains of RNase 7 that influence its activity against uropathogenic bacteria. A series of RNase 7 fragments were generated that contained different components of its secondary motifs starting from both the N terminus and the C terminus of RNase 7. We determined the antimicrobial properties of each fragment against both Gram-positive Staphylococcus saprophyticus and Gram-negative Escherichia coli and Proteus mirabilis. RNase 7 fragments displayed significant differences in their antimicrobial activity profiles. Compared to N-terminal fragments, C-terminal fragments showed uniformly decreased activity against Gram-negative E. coli and P. mirabilis and Gram-positive S. saprophyticus. Fragments that lack β-sheets 1, 3, and 4 also demonstrated significantly decreased activities. We have also identified one fragment with at least 4-fold increased potency against both E. coli and Staphylococcus compared to full-length peptide. We identified distinct regions of the peptide that are independently responsible for Gram-negative and Gram-positive activity. Our results suggest that distinct mechanisms are responsible for RNase 7's antimicrobial activity against various uropathogens.

Clinical characteristics of bacteraemia caused by extended-spectrum β-lactamase-producing Enterobacteriaceae in the era of CTX-M-type and KPC-type β-lactamases

A multicentre, case-control study was conducted to assess risk factors and patient outcomes of bacteraemia caused by Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) and Klebsiella pneumoniae carbapenemases (KPCs). One hundred and five and 20 patients with bacteraemia caused by ESBL-producing and KPC-producing organisms were matched to controls who had bacteraemia caused by non-ESBL/KPC-producing organisms, respectively. Independent risk factors for ESBL production included admission from a nursing home (OR 4.64; 95% CI 2.64–8.16), chronic renal failure (OR 2.09; 95% CI 1.11–3.92), the presence of a gastrostomy tube (OR 3.36; 95% CI 1.38–8.18), length of hospital stay before infection (OR 1.02; 95% CI 1.01–1.03), transplant receipt (OR 2.48; 95% CI 1.24–4.95), and receipt of antibiotics with Gram-negative activity in the preceding 30 days (OR 1.76; 95% CI 1.00–3.08). Twenty-eight-day crude mortality rates for patients infected with ESBL-producing or KPC-producing organisms and controls were 29.1% (34/117) and 19.5% (53/272), respectively (OR 1.70; 95% CI 1.04–2.80). On multivariate analysis, inadequate empirical therapy (OR 2.26; 95% CI 1.18–4.34), onset of bacteraemia while in the intensive-care unit (OR 2.74; 95% CI 1.47–5.11), Apache II score (OR 1.17; 95% CI 1.12–1.23) and malignancy (OR 2.66; 95% CI 1.31–5.41) were independent risk factors for mortality. CTX-M was the most common ESBL type in Escherichia coli, whereas SHV predominated in Klebsiella spp. and Enterobacter spp.

Pyridone Methylsulfone Hydroxamate LpxC Inhibitors for the Treatment of Serious Gram-Negative Infections

The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.

Synthesis, antibacterial activity, and toxicity of 7-(isoindolin-5-yl)-4-oxoquinoline-3-carboxylic acids. Discovery of the novel des-F(6)-quinolone antibacterial agent garenoxacin (T-3811 or BMS-284756).

The palladium-catalyzed cross-coupling reaction of 5-(tributylstannyl)isoindoline and its 1- and 3-methyl derivatives with 6-fluoro or 6-unsubstituted 7-bromo-1-cyclopropyl-8-methoxy (or difluoromethoxy)-4-oxoquinoline-3-carboxylate afforded the corresponding 1-cyclopropyl-7-(5-isoindolinyl)-4-oxoquinoline-3- carboxylic acids: 6-fluoro, 1a-7a and 6-nonfluoro, 1b-7b. The in vitro antibacterial spectra of the newly synthesized quinolones were mostly characterized by excellent Gram-positive activity against Staphylococcus aureus and Streptococcus pneumoniae including quinolone-resistant strains, and also by significant Gram-negative activity comparable to 7-(1-piperazinyl)fluoroquinolones. Comparative examinations of the in vitro antibacterial profiles and the in vivo toxicity in terms of intravenous lethality, micronuclei-inducing potential and convulsive activity provided 6-nonfluorinated 1-cyclopropyl-8-(difluoromethoxy)-7-(1-methylisoindolin-5-yl)-4- oxoquinoline-3-carboxylic acid [(+/-)-5b] as the candidate for evaluation of the stereoisomers. The enantiomers (R)-5b and (S)-5b were synthesized via the Suzuki coupling reaction of (R)- and (S)-1-methyl derivatives of 2-(triphenylmethyl)isoindolin-5-boronic acid with the corresponding 7-bromo-8-(difluoromethoxy)-4- oxoquinoline-3-carboxylate. The (R)-5b stereoisomer proved to be 2- to 4-fold more active than the (S)-5b stereoisomer against the organisms tested, with the exception of an equal potency observed with S. pneumoniae IID553 and Haemophilus influenzae ATCC49247. A noticeable in vitro antibacterial profile of (R)-5b was that it is 16- and 64-fold more active than levofloxacin (CAS 100986-85-4) and ciprofloxacin (CAS 86393-32-0), respectively, against Mycoplasma pneumoniae IID813 (MIC of 0.0313 microgram/ml), and 4-fold more active than ciprofloxacin and levofloxacin against Mycobacterium tuberculosis M-4 (MIC of 0.0313 microgram/ml). Additional studies indicate that (R)-5b (T-3811, CAS 194804-75-6) exhibits excellent antibacterial activity against a wide range of organisms including anaerobes and common respiratory pathogens, while demonstrating a high selectivity against the mammalian homolog topoisomerases. The methane-sulfonate of (R)-5b (T-3811ME, CAS 223652-90-2) is now undergoing clinical testings.

Comparative Effectiveness of Aminoglycosides, Polymyxin B, and Tigecycline for Clearance of Carbapenem-Resistant Klebsiella pneumoniae from Urine

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an increasingly common cause of health care-associated urinary tract infections. Antimicrobials with in vitro activity against CRKP are typically limited to polymyxins, tigecycline, and often, aminoglycosides. We conducted a retrospective cohort study of cases of CRKP bacteriuria at New York-Presbyterian Hospital from January 2005 through June 2010 to compare microbiologic clearance rates based on the use of polymyxin B, tigecycline, or an aminoglycoside. We constructed three active antimicrobial cohorts based on the active agent used and an untreated cohort of cases that did not receive antimicrobial therapy with Gram-negative activity. Microbiologic clearance was defined as having a follow-up urine culture that did not yield CRKP. Cases without an appropriate follow-up culture or that received multiple active agents or less than 3 days of the active agent were excluded. Eighty-seven cases were included in the active antimicrobial cohorts, and 69 were included in the untreated cohort. The microbiologic clearance rate was 88% in the aminoglycoside cohort (n = 41), compared to 64% in the polymyxin B (P = 0.02; n = 25), 43% in the tigecycline (P < 0.001; n = 21), and 36% in the untreated (P < 0.001; n = 69) cohorts. Using multivariate analysis, the odds of clearance were lower for the polymyxin B (odds ratio [OR], 0.10; P = 0.003), tigecycline (OR, 0.08; P = 0.001), and untreated (OR, 0.14; P = 0.003) cohorts than for the aminoglycoside cohort. Treatment with an aminoglycoside, when active in vitro, was associated with a significantly higher rate of microbiologic clearance of CRKP bacteriuria than treatment with either polymyxin B or tigecycline.

Discovery of vinylogous carbamates as a novel class of β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors

β-Ketoacyl-acyl carrier protein synthase III (FabH) catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase in most bacteria. The important role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of new FabH inhibitors. We first used a structure-based approach to develop 24 new vinylogous carbamates ( 4a– 15a, 4b– 15b) that target FabH for the development of new antibiotics in this paper. Potent FabH inhibitory and selective anti- Gram-negative bacteria activities were observed in most of these vinylogous carbamates. Especially, compound 6a and 7a showed the most potent FabH inhibitory activity with IC 50 of 2.6 and 3.3 μM, respectively. Docking simulation was performed to position compound 6a into the Escherichia coli FabH active site and the possible binding conformation of compounds has been proposed. The biological data and molecular docking indicated that compounds 6a and 7a were potent inhibitors of E. coli FabH as antibiotics deserving further research.

Present and Emerging Therapies for Methicillin-Resistant Staphylococcus aureus Skin and Soft Tissue Infections: Focus on Iclaprim

The management of skin and soft-tissue infections caused by multidrug resistant Gram-positive organisms, specifically methicillin-resistant Staphylococcus aureus (MRSA), continues to be a significant challenge for clinicians. Iclaprim is a diaminopyrimidine that has shown potent activity against various Gram-positive organisms, including MRSA, with limited Gram-negative activity similar to that of trimethoprim. Iclaprim has completed two Phase III trials with a submission of New Drug Application to the United States Food and Drug Administration (FDA) in 2008. Subsequently, a complete response letter not supporting the approval of iclaprim was released by the FDA. More recently, Acino Holding Ltd. has acquired the shares and data to iclaprim. Pending final draft guidance from the FDA for future studies, iclaprim may have a role in the management of skin and soft-tissue infections. A Medline search of articles through February 2011 and references of selected citations was conducted. Data from abstracts presented at the International Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America annual meetings were also appraised. This article reviews the antimicrobial profile, pharmacokinetic and pharmacodynamic properties, and available clinical data of iclaprim.

Preparation, gram-negative antibacterial activity, and hydrolytic stability of novel siderophore-conjugated monocarbam diols.

A novel series of monocarbam compounds exhibiting promising antibacterial activity against multidrug resistant Gram-negative microorganisms is reported, along with the synthesis of one such molecule MC-1 (1). Also reported are structure-activity relationships associated with the in vitro and in vivo efficacy of 1 and related analogues in addition to the hydrolytic stability of such compounds and possible implications thereof.

Decreased Antibiotic Utilization After Implementation of a Guideline for Inpatient Cellulitis and Cutaneous Abscess

Cellulitis and cutaneous abscess are among the most common infections leading to hospitalization, yet optimal management strategies have not been adequately studied. We hypothesized that implementation of an institutional guideline to standardize and streamline the evaluation and treatment of inpatient cellulitis and abscess would decrease antibiotic and health care resource utilization. A retrospective preintervention-postintervention study was performed to compare management before and after implementation of the guideline (January 1, 2007-December 31, 2007, and July 9, 2009-July 8, 2010). A total of 169 patients (66 with cellulitis, 103 with abscess) were included in the baseline cohort, and 175 (82 with cellulitis, 93 with abscess) were included in the intervention cohort. The intervention led to a significant decrease in use of microbiological cultures (80% vs 66%; P=.003) and fewer requests for inpatient consultations (46% vs 30%; P=.004). The median duration of antibiotic therapy decreased from 13 days (interquartile range [IQR], 10-15 days) to 10 days (IQR, 9-12 days) (P<.001). Fewer patients received antimicrobial agents with broad aerobic gram-negative activity (66% vs 36%; P<.001), antipseudomonal activity (28% vs 18%; P=.02), or broad anaerobic activity (76% vs 49%; P<.001). Clinical failure occurred in 7.7% and 7.4% of cases (P=.93), respectively. Implementation of a guideline for the management of inpatient cellulitis and cutaneous abscess led to shorter durations of more targeted antibiotic therapy and decreased use of resources without adversely affecting clinical outcomes.

Synthesis and antibacterial activity of amphiphilic lysine-ligated neomycin B conjugates

Amphiphilic lysine-ligated neomycin B building blocks were prepared by reductive amination of a protected C5″-modified neomycin B-based aldehyde and side chain-unprotected lysine or lysine-containing peptides. It was demonstrated that a suitably protected lysine-ligated neomycin B conjugate (NeoK) serves as a building block for peptide synthesis, enabling incorporation of aminoglycoside binding sites into peptides. Antibacterial testing of three amphiphilic lysine-ligated neomycin B conjugates against a representative panel of Gram-positive and Gram-negative strains demonstrates that C5″-modified neomycin-lysine conjugate retains antibacterial activity. However, in most cases the lysine-ligated neomycin B analogs display reduced potency against Gram-positive strains when compared to unmodified neomycin B or unligated peptide. An exception is MRSA where an eightfold enhancement was observed. When compared to unmodified neomycin B, the prepared lysine-neomycin conjugates exhibited a 4–8-fold enhanced Gram-negative activity against Pseudomonas aeruginosa and up to 12-fold enhanced activity was observed when compared to unligated reference peptides.

Skin and Soft‐Tissue Infections Requiring Hospitalization at an Academic Medical Center: Opportunities for Antimicrobial Stewardship

Although complicated skin and soft-tissue infections (SSTIs) are among the most common infections requiring hospitalization, their clinical spectrum, management, and outcomes have not been well described. We report a cohort of consecutive adult patients hospitalized for SSTI from 1 January through 31 December 2007 at an academic medical center. Cases meeting inclusion criteria were reviewed and classified as cellulitis, cutaneous abscess, or SSTI with additional complicating factors. In total, 322 patients were included; 66 (20%) had cellulitis, 103 (32%) had cutaneous abscess, and 153 (48%) had SSTI with additional complicating factors. Injection drug use, diabetes mellitus, and alcohol abuse were common comorbidities. Serum inflammatory markers were routinely measured and blood cultures and imaging studies were routinely performed in each group. Of 150 patients with a positive culture result for an abscess, deep tissue, or blood, Staphylococcus aureus or streptococci were identified in 145 (97%). Use of antibiotics with broad aerobic gram-negative activity (61%-80% of patients) or anaerobic activity (73%-83% of patients) was frequent in each group. The median duration of therapy for cellulitis, cutaneous abscess, and SSTI with additional complicating factors was 13 (interquartile range [IQR], 10-14), 13 (IQR, 10-16), and 14 (IQR, 11-17) days, respectively. Treatment failure, recurrence, or rehospitalization due to SSTI within 30 days occurred in 12.1%, 4.9%, and 9.2% of patients, respectively. Hospitalizations for SSTI were common; more than half were due to cellulitis or cutaneous abscess. Frequent use of potentially unnecessary diagnostic studies, broad-spectrum antibiotic therapy, and prolonged treatment courses in these patients suggest targets for antimicrobial stewardship programs.

Management of Aminoglycosides in the Intensive Care Unit

Antibacterial resistance is increasing throughout the world, while the development of new agents is slowly progressing. In addition, the increasing prevalence of fluoroquinolone resistance may force many practitioners to choose an aminoglycoside agent in gram-negative regimens. Aminoglycosides are bactericidal agents with potent activity against gram-negative infections and activity against gram-positive infections when added to a cell wall active antimicrobial-based regimen. These agents may be dosed multiple times a day or consolidated as high-dose, extended-interval dosing to maximize pharmacokinetic and pharmacodynamic properties to achieve possible improved efficacy with reduced toxicity. Clinical application includes the treatment of bacteremia, endocarditis, health-care and nosocomial pneumonias, intra-abdominal infections, and others. Nephrotoxicity and ototoxicity are potential risks of aminoglycoside therapy that may be minimized with serum monitoring and short courses of therapy.

Lactobacillus GG (LGG) Peptides Can Inhibit Antibiotic-Resistant Bacteria Growth

Background: We have recently reported that Lactobacillus GG (LGG) elaborates seven small peptides that exert both anti- Gram-negative and Gram-positive bactericidal activity. Among them, peptides NPSRQERR, VHTAPK and PDENK have higher activity than others. Here we further report the inhibitory function of these three peptides on antibiotic- resistant bacterial strains and preliminary structure-activity analysis. Methods: Peptides were synthesized, purified, and dissolved in related media. Lactobacillus GG conditioned medium was used as a positive control and media alone or homologous-conditioned medium were used as negative controls. A600 measurement was used to measure antibacterial activity. Results: LGG-derived peptides NPSRQERR, VHTAPK and PDENK were found to inhibit growth of kanamycin-resistant E. coli SM10 δpir and tetracycline-resistant E. coli TOPO10. Moreover, growth of methicillin-resistant Staphylococcus aureus (MRSA) was also found to be inhibited by peptides NPSEQERR, VHTAPK and PDENK. Structurefunction analyses revealed that the anti-bacterial properties of these peptides can be increased or decreased by modification of amino acid charge. Keywords: Lactobacillus GG, peptide, antibiotic-resistant bacteria, Methicillin resistant Staphylococcus aureus (MRSA)

In vitro activity of XF-73, a novel antibacterial agent, against antibiotic-sensitive and -resistant Gram-positive and Gram-negative bacterial species

The antibacterial activity of XF-73, a dicationic porphyrin drug, was investigated against a range of Gram-positive and Gram-negative bacteria with known antibiotic resistance profiles, including resistance to cell wall synthesis, protein synthesis, and DNA and RNA synthesis inhibitors as well as cell membrane-active antibiotics. Antibiotic-sensitive strains for each of the bacterial species tested were also included for comparison purposes. XF-73 was active [minimum inhibitory concentration (MIC) 0.25–4mg/L] against all of the Gram-positive bacteria tested, irrespective of the antibiotic resistance profile of the isolates, suggesting that the mechanism of action of XF-73 is unique compared with the major antibiotic classes. Gram-negative activity was lower (MIC 1mg/L to >64mg/L). Minimum bactericidal concentration data confirmed that the activity of XF-73 was bactericidal. Time–kill kinetics against healthcare-associated and community-associated meticillin-resistant Staphylococcus aureus isolates demonstrated that XF-73 was rapidly bactericidal, with >5log10 kill obtained after 15min at 2× MIC, the earliest time point sampled. The post-antibiotic effect (PAE) for XF-73 under conditions where the PAE for vancomycin was <0.4h was found to be >5.4h. XF-73 represents a novel broad-spectrum Gram-positive antibacterial drug with potentially beneficial characteristics for the treatment and prevention of Gram-positive bacterial infections.

Synthesis, spectral studies, and antimicrobial activity of binary and ternary Cu(II), Ni(II), and Fe(III) complexes of new hexadentate Schiff bases derived from 4,6-diacetylresorcinol and amino acids

Two new hexadentate N2O4 donor Schiff bases, H4L1 and H4L2, were synthesized by condensation of 4,6-diacetylresorcinol with glycine and alanine, respectively. The structures of the ligands were elucidated by elemental analyses, IR, 1H NMR, electronic, and mass spectra. Reactions of the Schiff bases with copper(II), nickel(II), and iron(III) nitrates in 1 : 2 molar ratio gave binuclear metal complexes and, in the presence of 8-hydroxyquinoline (8-HQ) or 1,10-phenanthroline (Phen) as secondary ligands (L′), mixed-ligand complexes in two molar ratios 1 : 2 : 2 and 1 : 2 : 1 (L1/L2 : M : L′). The complexes were characterized by elemental and thermal analyses, IR, electronic, mass, and ESR spectral studies, as well as conductivity and magnetic susceptibility measurements. The spectroscopic data reveal that the Schiff-base ligands were dibasic or tetrabasic hexadentate ligands. The coordination sites with the metal ions are two azomethine nitrogens, two oxygens of phenolic groups, and two oxygens of carboxylic groups. Copper(II) complexes were octahedral and square planar while nickel(II) and iron(III) complexes were octahedral. The Schiff bases, H4L1 and H4L2, and some of their metal complexes showed antibacterial activity towards Gram-positive (Staphylococcus aureus and Streptococcus pyogenes) and Gram-negative (Pseudomonas fluorescens and Pseudomonas phaseolicola) bacteria and antifungal activity towards the fungi Fusarium oxysporium and Aspergillus fumigatus.