Antibiotic-resistant Gram-negative Bacteria Research Articles

Virtual Screening for Potential Inhibitors of CTX-M-15 Protein of Klebsiella pneumoniae.

The Gram-negative bacterium Klebsiella pneumoniae, responsible for a wide variety of nosocomial infections in immuno-deficient patients, involves the respiratory, urinary and gastrointestinal tract infections and septicemia. Extended spectrum β-lactamases (ESBL) belong to β-lactamases capable of conferring antibiotic resistance in Gram-negative bacteria. CTX-M-15, a prevalent ESBL reported from Enterobacteriaceae including K. pneumoniae, was selected as a potent anti-bacterial target. To identify the novel drug-like compounds, structure-based screening procedure was employed against downloaded drug-like compounds from ZINC database. An acronym for "ZINC" is not commercial. The docking free energy values were investigated and compared to the known inhibitor Avibactam. Six best novel drug-like compounds were selected and their hydrogen bindings with the receptor were determined. Based on the binding efficiency mode, three among these six identified most potential inhibitors, ZINC21811621, ZINC93091917 and ZINC19488569, were predicted as potential competitive inhibitors against CTX-M-15 compared to Avibactam. These three inhibitors may provide a framework for the experimental studies to develop anti-Klebsiella novel drug candidates targeting CTX-M-15.

Antibacterial Compounds from Marine Bacteria, 2010-2015.

This review summarizes the reports on antibacterial compounds that have been obtained from marine-derived bacteria during the period 2010-2015. Over 50 active compounds were isolated during this period, most of which (69%) were obtained from Actinobacteria. Several compounds were already known, such as etamycin A (11) and nosiheptide (65), and new experiments with them showed some previously undetected antibacterial activities, highlighting the fact that known natural products may be an important source of new antibacterial leads. New broad-spectrum antibacterial compounds were reported with activity against antibiotic resistant Gram-positive and Gram-negative bacteria. Anthracimycin (33), kocurin (66), gageotetrins A-C (72-74), and gageomacrolactins 1-3 (86-88) are examples of compounds that display promising properties and could be leads to new antibiotics. A number of microbes produced mixtures of metabolites sharing similar chemical scaffolds, and structure-activity relationships are discussed.

The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace.

Carbapenem-resistant Enterobacteriaceae (CRE) are a serious public health threat. Infections due to these organisms are associated with significant morbidity and mortality. Mechanisms of drug resistance in gram-negative bacteria (GNB) are numerous; β-lactamase genes carried on mobile genetic elements are a key mechanism for the rapid spread of antibiotic-resistant GNB worldwide. Transmissible carbapenem-resistance in Enterobacteriaceae has been recognized for the last 2 decades, but global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is a more recent problem that, once initiated, has been occurring at an alarming pace. In this article, we discuss the evolution of CRE, with a focus on the epidemiology of the CPE pandemic; review risk factors for colonization and infection with the most common transmissible CPE worldwide, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae; and present strategies used to halt the striking spread of these deadly pathogens.

RND efflux pump mediated antibiotic resistance in Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa: a major issue worldwide.

Therapeutic failures against diseases due to resistant Gram-negative bacteria have become a major threat nowadays as confirmed by surveillance reports across the world. One of the methods of development of multidrug resistance in Escherichia coli and Pseudomonas aeruginosa is by means of RND efflux pumps. Inhibition of these pumps might help to combat the antibiotic resistance problem, for which the structure and regulation of the pumps have to be known. Moreover, judicious antibiotic use is needed to control the situation. This paper focuses on the issue of antibiotic resistance as well as the structure, regulation and inhibition of the efflux pumps present in Escherichia coli and Pseudomonas aeruginosa.

The Development of an IMP Metallo-β-lactamase Detection Assay Using a Bioinformatic Approach

BackgroundCarbapenem antibiotic resistance in Gram-negative bacteria is becoming increasingly common. One such resistance gene, IMP metallo-β-lactamase, has been found worldwide. With 48 different IMP alleles across many genera of bacteria, no known assay can detect all 48 IMP alleles. We developed a PCR-based assay to detect IMP genes using a novel bioinformatic approach to design primers that would recognize all gene variants.MethodsComputer simulation of primers was accomplished by using common PCR primer design heuristics as parameters. Following primer simulation, an all-against-all gene comparison was done to calculate potential primer sets. The minimum number of primer sets required to detect all IMP genes was subsequently found by iterative deduction. The predicted primer sets were tested against 7 IMP-producing bacterial isolates (IMP-1, 4, 7, 8, 14, 18, 27 from Serratia, Enterobacteriaceae, Pseudomonas, and Klebsiella spp.) and one synthesized gene of IMP-35. These isolates were chosen to represent the full genetic spectrum of the IMP family. The remaining 40 genes were evaluated based on gene sequences obtained from GenBank.ResultsThe in silico analysis showed 6 primer sets were needed to detect all known IMP genes. PCR amplification of template DNA isolated from the 8 strains showed that primer sets 1 and 4 could detect all 8 IMP isolates while the remaining 4 sets (2, 3, 5, 6) had distinct amplification patterns that could be used together to identify a specific IMP gene group. Effectiveness of these primer sets in IMP identification was demonstrated by testing a clinical isolate containing an unidentified carbapenem resistant bacterium. The IMP-27 gene was identified by PCR amplification using the IMP-specific primers designed and confirmed by sequence analysis.ConclusionA bioinformatic approach can be used to create an assay for bacterial resistance. The assay developed with this approach can detect and classify all known IMP metallo-β-lactamase genes in carbapenem resistant Gram-negative bacteria. Such information could aid in guiding treatment and evaluating the epidemiology of IMP-producing bacteria.Disclosures All authors: No reported disclosures.

Associations Between Timeliness of Therapy and Clinical and Economic Outcomes Among Patients With Serious Infections Due to Gram-negative Bacteria (GNB): How Much Does Delayed Appropriate Therapy (DAT) Matter?

BackgroundPatients with serious GNB infections who receive DAT have worse outcomes. Most studies that have examined this issue include both antibiotic-resistant and susceptible pathogens. It is difficult to assign causality as DAT is correlated with resistance, which is associated with poorer prognosis. Our objective was to assess association between DAT and outcomes among patients with GNB infection, stratified by antibiotic susceptibility status.MethodsHospitalized adults between 7/2011–9/2014 were identified from Premier Hospital Database. Patients were diagnosed with complicated urinary tract infection, complicated intra-abdominal infection, hospital-associated pneumonia, or bloodstream infection, and had a positive culture for GNB from a site consistent with infection type (date of culture draw was index date). Patients were required to receive antibiotics on this date or ≤2 days after. Delayed therapy was defined as no receipt of an antibiotic with microbiologic activity during this period. Patients were stratified by antibiotic-resistant GNB (Third-generation cephalosporin-resistant Enterobacteriaceae, carbapenem‐resistant (CR) Enterobacteriaceae, CR Pseudomonas sp., or multi‐drug-resistant Pseudomonas sp.) vs. antibiotic-susceptible GNB counterparts. Inverse probability weighting and multivariate regression analyses were used to estimate the association between DAT and outcomes. Logistic models were used for composite mortality (in-hospital death or discharge to hospice) and discharge to home. Generalized linear models were used for post-index duration of antibiotic therapy, hospital length of stay (LOS), and costs.ResultsA total of 6,055 resistant and 50,302 susceptible infections were identified; 2,800 and 16,585, respectively, received DAT. In multivariate analyses, DAT was associated with worse outcomes, including a 20% increased risk of composite mortality and an approximate 70% increase in LOS and total costs, respectively. The relative impact of DAT was nearly identical by antibiotic-resistant status (Figure).ConclusionOur study indicates that DAT is independently associated with poorer outcomes in serious infections due to GNB, irrespective of resistance status.Disclosures N. G. Bonine, Allergan plc: Employee, Salary. A. Berger, Allergan plc: Consultant, Consulting fee. R. Wang, Evidera: Employee, Salary. T. Bhagnani, Allergan plc: Consultant, Consulting fee. P. Gillard, Allergan plc: Employee, Salary. T. Lodise, Allergan plc: Consultant and Scientific Advisor, Consulting fee and Speaker honorarium.

Engineered Cationic Antimicrobial Peptides Containing Cholesterol Interacting Motifs to Target Viral Envelopes

In recent decades, efforts have been made to rationally design antimicrobial peptides (AMPs) for use as alternative antimicrobial therapeutics. The de novo engineered cationic antimicrobial peptide (eCAP) WLBU2 is a 24-residue peptide composed of arginine, tryptophan, and valine computationally sequenced to form an optimized amphipathic helix. Antimicrobial activity of WLBU2 is predicted to transpire through peptide interaction with lipid membranes leading to bilayer disruption. Antibacterial activity of WLBU2 has been demonstrated against a widerange of antibiotic resistant Gram-positive and Gram-negative bacteria. Natural antimicrobial peptides have been shown to inactivate enveloped viruses, albeit at higher peptide concentrations than required for bacterial killing. While viral envelopes do not have the same negative surface charge presumed to be the basis for antibacterial activity of WLBU2, most mammalian virus membranes are enriched for cholesterol relative to host cells. Based on this structural feature, WLBU2 was modified by addition of cholesterol recognition amino acid consensus (CRAC) motifs to increase antiviral activity against enveloped mammalian viruses. The CRAC-modified WLBU2 peptides were tested against human immunodeficiency virus (HIV), influenza A, and dengue virus (DENV) to assess antiviral activity against viruses with markedly different levels of surface lipid exposure and against mammalian cells to assess potential cytotoxicity. Antiviral activity was enhanced by the CRAC motif and demonstrated the highest efficacy against DENV and lowest against HIV, inverse to the level of surface membrane exposure. These studies reveal for the first time an unexpected range of engineered peptide activity against a broad group of different target viruses with vastly different membrane composures and indicate the ability of CRAC motif modification to enhance antiviral activity.

Hastane Kanalizasyonlarından İzole Edilen Gram-negatif Bakterilerin Tiplendirilmesi ve Çoklu Antibiyotik Dirençliliklerinin Saptanması

In this study it was aimed to determine the microbial diversity and level of antibiotic resistance patterns of Gram-negative bacterial isolates from the hospital sewages. The 219 Gram-negative bacterial isolates to 16 different antibiotics (belonging 10 classes), was investigated by agar diffusion method. A total of 18 species of bacteria were isolated: the most common strains isolated from all samples were Klebsiella oxytoca (27.4%), Klebsiella pneumoniae (20.5%) and Escherichia coli (20.1%). There was a high incidence of resistance to ampicillin (98.6%), streptomycin (95.9%) and erythromycin (90.0%), and a low incidence of resistance to cefepim (13.2%), imipenem (5.0%) and meropenem (3.2%). 35.6% of all bacteria isolated from hospital sewage were resistant to 9 different antibiotics. The multiple antibiotic resistances (MAR) index ranged from 0.25 to 0.94. Results show that hospital sewages have a significant proportion of antibiotic resistant Gram-negative bacteria, and these bacteria constitute a potential risk for public health.

Antibiotic Resistance and Regulation of the Gram-Negative Bacterial Outer Membrane Barrier by Host Innate Immune Molecules.

ABSTRACTThe Gram-negative outer membrane is an important barrier that provides protection against toxic compounds, which include antibiotics and host innate immune molecules such as cationic antimicrobial peptides. Recently, significant research progress has been made in understanding the biogenesis, regulation, and functioning of the outer membrane, including a recent paper from the laboratory of Dr. Brett Finlay at the University of British Columbia (J. van der Heijden et al., mBio 7:e01238-16, 2016, http://dx.doi.org/10.1128/mBio.01541-16). These investigators demonstrate that toxic oxygen radicals, such as those found in host tissues, regulate outer membrane permeability by altering the outer membrane porin protein channels to regulate the influx of oxygen radicals as well as β-lactam antibiotics. This commentary provides context about this interesting paper and discusses the prospects of utilizing increased knowledge of outer membrane biology to develop new antibiotics for antibiotic-resistant Gram-negative bacteria.

A 980 nm driven photothermal ablation of virulent and antibiotic resistant Gram-positive and Gram-negative bacteria strains using Prussian blue nanoparticles

A 980nm laser-driven antimicrobial photothermal therapy using poly(vinylpyrrolidone) -coated Prussian Blue nanoparticles (PVP/PB NPs) is demonstrated. This approach allows an efficient eradication of a virulent strain of Gram-negative Escherichia coli (E. coli) associated with urinary tract infection as well as for the ablation of antibiotic resistant pathogens such as methicillin resistant Staphylococcus aureus (MRSA) and extended spectrum β-lactamase (ESBL) E. coli. Interestingly the 980nm irradiation exhibits minimal effect on mammalian cells up to a PVP/PB NPs concentration of 50μgmL−1, while at this concentration bacteria are completely eradicated. This feature is certainly very promising for the selective targeting of bacteria over mammalian cells.

Artemisia herba-alba Asso and Cymbopogon citratus (DC.) Stapf essential oils and their capability to restore antibiotics efficacy

Inhibition of bacterial efflux mechanisms has been investigated as a promising target to combat the bacterial resistance to antibiotics. The present work investigated the ability of Artemisia herba-alba and Cymbopogon citratus essential oils (EOs) to inhibit efflux pumps of some selected antibiotic-resistant Gram-negative bacteria. The chemical profiles of tested EOs were evaluated by GC–MS. The major constituents of the oils were chrysanthenone (47.0%), camphor (24.0%), and verbenone (7.2%) in A. herba-alba EO and geranial (46.3%), neral (35.2%), and geraniol (5.4%) in C. citratus EO. Antibacterial tests showed that these EOs had high antibacterial activity. This activity was significantly enhanced in the presence of an efflux pump inhibitor, phenylalanine arginyl ß-naphthylamide (PAßN). When combined with PAßN, the MIC values against EA27 and AG102 (strains overexpressing efflux pumps) were decreased 32-fold and >32-fold, respectively, for A. herba-alba, and 512-fold and 1024-fold, respectively, for C. citratus EO. The involvement of a lipopolysaccharide (LPS) structure in the resistance to the active compounds of the studied EOs was also demonstrated in Salmonella LPS deep-rough mutants. Moreover, the combination of A. herba-alba and C. citratus EOs, at a low concentration, reduced significantly chloramphenicol MIC 2–4-fold, 4-fold and 8–16-fold, respectively, for EAEP294 (deleted of AcrAB), EA27 and AG102. For Salmonella strains, all tested combinations recorded a gain greater than or equal to 64-fold. It was concluded that these EOs can alter efflux pump activity and may be good candidates for the development of new chemosensitizer drugs able to restore antibiotic activity of some drug-resistant Gram-negative bacteria.

Rapid Detection of Antibiotic Resistance in Gram-Negative Bacteria Through Assessment of Changes in Cellular Morphology.

Rapid antimicrobial susceptibility testing has the potential to improve patient outcomes and reduce healthcare-associated costs. In this study, a novel assay based on bacterial cell elongation after exposure to an antibiotic (ceftazidime) was evaluated for its ability to rapidly detect resistance in Gram-negative bacteria. The assay was used to detect resistance in a large collection of strains containing 320 clinical isolates of Acinetobacter baumannii, 171 clinical isolates of Klebsiella pneumoniae, and 212 clinical isolates of Pseudomonas aeruginosa, and the results were compared to those obtained using standard antimicrobial susceptibility testing methods. The assay identified ceftazidime-resistant strains with 100% sensitivity and 100% specificity for A. baumannii, 100% sensitivity and 97.2% specificity for K. pneumoniae, and with 82.3% sensitivity and 100% specificity for P. aeruginosa. Importantly, results were obtained in 1 hour 15 minutes from exponentially growing cultures. This study demonstrates that changes in cell length are highly correlated with phenotypic antibiotic susceptibility determined using standard susceptibility testing methods. This study therefore provides proof-of-concept that changes in cell morphology can be used as the basis for rapid detection of antibiotic resistance and provides the basis for the development of novel rapid diagnostics for the detection of antibiotic resistance.

Effect of Periodontal Therapy With Amoxicillin-Metronidazole on Pharyngeal Carriage of Penicillin- and Erythromycin-Resistant Viridans Streptococci.

Previous studies have focused on antibiotic resistance of Gram-negative bacteria before and after periodontal therapy. The purpose of this analysis is to assess changes in resistance patterns of the commensal Gram-positive microbiota. The viridans group streptococci (VGS) have been suggested to serve as reservoirs of resistance genes for more pathogenic streptococci and may be implicated in some non-oral infections. In this randomized clinical trial, 80 patients with periodontitis are distributed randomly into two groups. In group A, patients received 375 mg amoxicillin and 500 mg metronidazole three times per day for 7 days during the non-surgical treatment phase (T1). In group B, the antibiotics were administered during the surgical phase (T2). Resistance of VGS to penicillin and erythromycin was determined by the epsilometer test. At baseline, VGS from 12.5% (group A) and 11.8% (group B) of patients had a minimum inhibitory concentration (MIC) >2 μg/mL to penicillin. Three months after T1, VGS from 15.6% and 16.7% of patients had an MIC >2 μg/mL, respectively. Six months after T2 VGS from 5.9% and 5.9% and 12 months after T2 VGS from 6.1% and 6.3% patients had an MIC >2 μg/mL. There was no effect of therapy with antibiotics, administered either in T1 or T2, on the carriage of penicillin-resistant VGS. Erythromycin resistance was high at baseline and remained unchanged throughout the study. MICs for penicillin and erythromycin were correlated (P <0.05). Amoxicillin plus metronidazole did not significantly affect the resistance pattern of the VGS to penicillin or erythromycin.

Relationship of various infection control interventions to the prevalence of multidrug-resistant Pseudomonas aeruginosa among U.S. hospitals

Health care-associated infections caused by antibiotic-resistant gram-negative bacteria, such as Pseudomonas aeruginosa, are an emerging and increasingly important public health threat. However, there are very few studies that examine the relationships between antimicrobial resistance strategies and interventions and the prevalence of antibiotic-resistant and multidrug-resistant strains of Pseudomonas. The membership of the Association for Professionals in Infection Control and Epidemiology was invited to participate in a Web-based survey of U.S. acute care hospital infection preventionists. A final sample of 225 completed responses was analyzed using correlational techniques. Resistance to gentamicin (r = 0.17, P = .01), imipenem (r = 0.18, P = .02), ceftazidime (r = 0.20, P = .03), and ciprofloxacin (r = 0.15, P = .03) all showed significant direct associations with epidemiologic investigation using molecular testing. A significant inverse relationship was found between resistance to ceftazidime and effective efforts in the identification and isolation of infected patients (r = -0.18, P = .02). The finding of significant direct relationships between antimicrobial resistance and epidemiologic investigations using molecular testing suggests that the increased burden of resistance is associated with molecular testing rather than the intervention driving down rates. Effective identification and isolation of infected patients appeared to be associated with lower resistance rates. Further research is needed to uncover causal relationships.

Increase in Antibiotic-Resistant Gram-Negative Bacterial Infections in Febrile Neutropenic Children.

BackgroundThe incidence of bacteremia caused by Gram-negative bacteria has increased recently in febrile neutropenic patients with the increase of antibiotic-resistant Gram-negative bacterial infections. This study aimed to identify the distribution of causative bacteria and the proportion of antibiotic-resistant bacteria in bacteremia diagnosed in febrile neutropenic children.Materials and MethodsThe medical records of febrile neutropenic children diagnosed with bacteremia between 2010 and 2014 were retrospectively reviewed. The causative bacteria and proportion of antibiotic-resistant bacteria were investigated and compared yearly during the study period. The clinical impact of antibiotic-resistant bacterial infections was also determined.ResultsA total of 336 bacteremia episodes were identified. During the entire study period, 181 (53.9%) and 155 (46.1%) episodes were caused by Gram-negative and Gram-positive bacteria, respectively. Viridans streptococci (25.9%), Klebsiella spp. (16.7%), and Escherichia coli (16.4%) were the most frequent causative bacteria. The overall distribution of causative bacteria was not significantly different annually. Antibiotic-resistant bacteria were identified in 85 (25.3%) episodes, and the proportion of antibiotic-resistant bacteria was not significantly different annually. Extended-spectrum β-lactamase-producing E. coli and Klebsiella spp. were most common among antibiotic-resistant Gram-negative bacteria, and they accounted for 30.6% (n = 34) of the identified E. coli and K. pneumoniae. Methicillin-resistant coagulase-negative staphylococci were most common among antibiotic-resistant Gram-positive bacteria, and it accounted for 88.5% (n = 23) of the identified coagulase-negative staphylococci. Antibiotic-resistant bacterial infections, especially antibiotic-resistant Gram-negative bacterial infections, caused significantly higher mortality due to bacteremia compared with non-antibiotic-resistant bacterial infections (P <0.001).ConclusionRecently, Gram-negative bacteria caused more bacteremia cases than Gram-positive bacteria in febrile neutropenic children, and antibiotic-resistant Gram-negative bacterial infections increased. Antibiotic-resistant bacterial infections caused poorer prognosis compared with non-antibiotic-resistant bacterial infections, and therefore, continuous surveillance for changing epidemiology of antibiotic-resistant bacterial infections and their clinical impact is necessary.

Violet 405 nm light: A novel therapeutic agent against β-lactam-resistant Escherichia coli.

Approximately 1.7 million patients are affected by hospital-acquired infections every year in the United States. The increasing prevalence of multidrug-resistant bacteria associated with these infections prompts the investigation of alternative sterilization and antibacterial therapies. One method currently under investigation is the antibacterial properties of visible light. This study examines the effect of a visible light therapy (VLT) on β-lactam-resistant Escherichia coli, a common non-skin flora pathogen responsible for a large percentage of indwelling medical device-associated clinical infection. 405 nm light-emitting diodes were used to treat varying concentrations of a common laboratory E. coli K-12 strain transformed with the pCIG mammalian expression vector. This conferred ampicillin resistance via expression of the β-lactamase gene. Bacteria were grown on sterile polystyrene Petri dishes plated with Luria-Bertani broth. Images of bacterial growth colonies on plates were processed and analyzed using ImageJ. Irradiance levels between 2.89 ± 0.19 and 9.45 ± 0.63 mW cm(-2) and radiant exposure levels between 5.60 ± 0.39 and 136.91 ± 4.06 J cm(-2) were tested. VLT with variable irradiance and constant treatment time (120 minutes) demonstrated significant reduction (P < 0.001) in E. coli between an irradiance of 2.89 mW cm(-2) (81.70%) and 9.37 mW cm(-2) (100.00%). Similar results were found with variable treatment time with constant irradiance. Log10 reduction analysis produced between 1.98 ± 0.53 (60 minute treatment) and 6.27 ± 0.54 (250 minute treatment) log10 reduction in bacterial concentration (P < 0.001). We have successfully demonstrated a significant bacterial reduction using high intensity 405 nm light. Illustrating the efficacy of this technology against a β-lactam-resistant E. coli is especially relevant to the need for novel methods of sterilization in healthcare settings. These results suggest that VLT using 405 nm light could be a suitable clinical option for eradication of β-lactam-resistant E. coli. Visible light kills statistically significant concentrations of E. coli. Antibiotic-resistant Gram-negative bacteria exhibits sensitivity to 405 nm light. Greater than 6 log10 reduction in β-lactam-resistant E. coli when treated with visible light therapy.

THE ANTIBACTERIAL ACTIVITY OF OFFICINAL HERBS IN REGARD TO EXTENSIVELY ANTIBIOTIC-RESISTANT GRAM-NEGATIVE RODS

Objective: to estimate the antibacterial activity of officinal herbs available in Belarus in regard to extensively antibiotic-resistant Gram-negative bacteria. Material and methods . Minimal inhibitory concentrations and minimal bactericidal concentrations of water infusions from officinal medicinal herbs in regards to antibiotic-resistant and antibiotic-sensitive strains of Gram-negative rods have been determined. Results. 4 out of the 17 herbs revealed the expressed antibacterial activity in regards to Gram-negative non-fermenting rods. The herbs did not reveal any antibacterial activity of water infusions in regard to K. pneumoniae . Conclusion. The revealed data on the antibacterial activity make it possible to recommend medicinal herbs for additional local application along with current systemic antibiotic therapy.

Investigational Agents for the Treatment of Gram-Negative Bacterial Infections: A Reality Check.

Antibiotic-resistant Gram-negative bacteria are, arguably, the most difficult organisms to treat, with a limited number of new antibiotics in the development pipeline. Currently 24 new agents in phase 1, phase 2, or phase 3 clinical development were identified for the potential treatment of infections caused by Gram-negative bacteria. Of these agents, most are improved iterations of known antibiotic classes, including new aminoglycosides, β-lactams, β-lactamase inhibitors, quinolones, and tetracyclines with greater potency or a broader spectrum of activity. However, novel structures also appear, with host defense peptide mimetics, boronic acid, and bridged diazabicyclooctane β-lactamase inhibitors and unique bacterial topoisomerase inhibitors. Most of the new agents have received a Qualified Infectious Disease Product (QIDP) designation that may help to accelerate FDA drug approvals. Because resistance will inevitably arise to any antibacterial agent, it will be necessary to continue to identify additional new agents in the future.

Binding site feature description of 2-substituted benzothiazoles as potential AcrAB-TolC efflux pump inhibitors in E. coli

The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.

Impact after 3 years of application of enteral paromomycin to eradicate colistin and carbepemenase resistant microrganisms in rectal colonization to prevent ICU infections

Emergence of carbapemenases and their worldwide distribution has worsens the clinical scenario of antibiotic resistance in Gram-negative bacteria. Selective Digestive Decontamination (SDD) has been used to prevent development of nosocomial colonization and infections in ICU patients. However, rectal colonization with multirresistant bacteria is a serious concern with SDD. An effective enteral antimicrobial treatment in this scenario is still lacking and it might contribute to prevent systemic nosocomial infections.