scholarly journals Loci Encoding Compounds Potentially Active against Drug-Resistant Pathogens amidst a Decreasing Pool of Novel Antibiotics

2019 ◽  
Vol 85 (23) ◽  
Author(s):  
Joseph Basalla ◽  
Payel Chatterjee ◽  
Elizabeth Burgess ◽  
Mahnur Khan ◽  
Emily Verbrugge ◽  
...  
Keyword(s):  
Natural Products ◽  
Gene Clusters ◽  
Multidrug Resistant ◽  
Antagonistic Activity ◽  
World Health ◽  
Drug Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Health Organization ◽  
Novel Antibiotics

ABSTRACT Since the discovery of penicillin, microbes have been a source of antibiotics that inhibit the growth of pathogens. However, with the evolution of multidrug-resistant (MDR) strains, it remains unclear if there is an abundant or limited supply of natural products to be discovered that are effective against MDR isolates. To identify strains that are antagonistic to pathogens, we examined a set of 471 globally derived environmental Pseudomonas strains (env-Ps) for activity against a panel of 65 pathogens including Achromobacter spp., Burkholderia spp., Pseudomonas aeruginosa, and Stenotrophomonas spp. isolated from the lungs of cystic fibrosis (CF) patients. From more than 30,000 competitive interactions, 1,530 individual inhibitory events were observed. While strains from water habitats were not proportionate in antagonistic activity, MDR CF-derived pathogens (CF-Ps) were less susceptible to inhibition by env-Ps, suggesting that fewer natural products are effective against MDR strains. These results advocate for a directed strategy to identify unique drugs. To facilitate discovery of antibiotics against the most resistant pathogens, we developed a workflow in which phylogenetic and antagonistic data were merged to identify strains that inhibit MDR CF-Ps and subjected those env-Ps to transposon mutagenesis. Six different biosynthetic gene clusters (BGCs) were identified from four strains whose products inhibited pathogens including carbapenem-resistant P. aeruginosa. BGCs were rare in databases, suggesting the production of novel antibiotics. This strategy can be utilized to facilitate the discovery of needed antibiotics that are potentially active against the most drug-resistant pathogens. IMPORTANCE Carbapenem-resistant P. aeruginosa is difficult to treat and has been deemed by the World Health Organization as a priority one pathogen for which antibiotics are most urgently needed. Although metagenomics and bioinformatic studies suggest that natural bacteria remain a source of novel compounds, the identification of genes and their products specific to activity against MDR pathogens remains problematic. Here, we examine water-derived pseudomonads and identify gene clusters whose compounds inhibit CF-derived MDR pathogens, including carbapenem-resistant P. aeruginosa.

scholarly journals The Acinetobacter baumannii Znu System Overcomes Host-Imposed Nutrient Zinc Limitation

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Laura E. Hesse ◽  
Zachery R. Lonergan ◽  
William N. Beavers ◽  
Eric P. Skaar
Keyword(s):  
Acinetobacter Baumannii ◽  
Defense Mechanisms ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
World Health ◽  
Content Type ◽  
Nutritional Immunity ◽  
Essential Nutrient ◽  
Health Organization

ABSTRACT Acinetobacter baumannii is an opportunistic bacterial pathogen capable of causing a variety of infections, including pneumonia, sepsis, wound, and burn infections. A. baumannii is an increasing threat to public health due to the prevalence of multidrug-resistant strains, leading the World Health Organization to declare A. baumannii a “Priority 1: Critical” pathogen, for which the development of novel antimicrobials is desperately needed. Zinc (Zn) is an essential nutrient that pathogenic bacteria, including A. baumannii, must acquire from their hosts in order to survive. Consequently, vertebrate hosts have defense mechanisms to sequester Zn from invading bacteria through a process known as nutritional immunity. Here, we describe a Zn uptake (Znu) system that enables A. baumannii to overcome this host-imposed Zn limitation. The Znu system consists of an inner membrane ABC transporter and an outer membrane TonB-dependent receptor. Strains of A. baumannii lacking any individual Znu component are unable to grow in Zn-starved conditions, including in the presence of the host nutritional immunity protein calprotectin. The Znu system contributes to Zn-limited growth by aiding directly in the uptake of Zn into A. baumannii cells and is important for pathogenesis in murine models of A. baumannii infection. These results demonstrate that the Znu system allows A. baumannii to subvert host nutritional immunity and acquire Zn during infection.

scholarly journals Avibactam Restores the Susceptibility of Clinical Isolates of Stenotrophomonas maltophilia to Aztreonam

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Maria F. Mojica ◽  
Krisztina M. Papp-Wallace ◽  
Magdalena A. Taracila ◽  
Melissa D. Barnes ◽  
Joseph D. Rutter ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
World Health ◽  
Combination Therapies ◽  
Content Type ◽  
Medical Need ◽  
The World ◽  
Health Organization

ABSTRACT Stenotrophomonas maltophilia is an emerging opportunistic pathogen, classified by the World Health Organization as one of the leading multidrug-resistant organisms in hospital settings. The need to discover novel compounds and/or combination therapies for S. maltophilia is urgent. We demonstrate the in vitro efficacy of aztreonam-avibactam (ATM-AVI) against S. maltophilia and kinetically characterize the inhibition of the L2 β-lactamase by avibactam. ATM-AVI overcomes aztreonam resistance in selected clinical strains of S. maltophilia, addressing an unmet medical need.

scholarly journals Drug-Resistant Tuberculosis 2020: Where We Stand

2020 ◽  
Vol 10 (6) ◽  
pp. 2153 ◽  
Author(s):  
Angelo Iacobino ◽  
Lanfranco Fattorini ◽  
Federico Giannoni
Keyword(s):  
Molecular Mechanisms ◽  
Drug Distribution ◽  
Multidrug Resistant ◽  
Diagnostic Methods ◽  
World Health ◽  
Drug Resistant ◽  
Comprehensive Overview ◽  
Resistant Tuberculosis ◽  
Health Organization ◽  
Incident Cases

The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods.

scholarly journals New β-Lactam–β-Lactamase Inhibitor Combinations

2020 ◽  
Vol 34 (1) ◽  
Author(s):  
Dafna Yahav ◽  
Christian G. Giske ◽  
Alise Grāmatniece ◽  
Henrietta Abodakpi ◽  
Vincent H. Tam ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Treatment Option ◽  
Clinical Data ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Lactamase Inhibitor

SUMMARY The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

scholarly journals Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives

2019 ◽  
Vol 28 (152) ◽  
pp. 190035 ◽  
Author(s):  
Emanuele Pontali ◽  
Mario C. Raviglione ◽  
Giovanni Battista Migliori
Keyword(s):  
Multidrug Resistant ◽  
New Drugs ◽  
World Health ◽  
Drug Resistant ◽  
Optimal Outcomes ◽  
Resistant Tuberculosis ◽  
Prolonged Duration ◽  
Mdr Tb ◽  
Revised Definitions ◽  
Health Organization

Over the past few decades, treatment of multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB) has been challenging because of its prolonged duration (up to 20–24 months), toxicity, costs and sub-optimal outcomes.After over 40 years of neglect, two new drugs (bedaquiline and delamanid) have been made available to manage difficult-to-treat MDR-/XDR-TB cases. World Health Organization (WHO) guidelines published in March 2019 endorsed the possibility of treating MDR-TB patients with a full oral regimen, following previous guidelines published in 2016 which launched a shorter regimen lasting 9–10 months.The objectives of this article are to review the main achievements in MDR-TB treatment through the description of the existing WHO strategies, to discuss the main ongoing trials and to shed light on potential future scenarios and revised definitions necessary to manage drug-resistant TB.

scholarly journals Synergistic Effects and Antibiofilm Properties of Chimeric Peptides against Multidrug-Resistant Acinetobacter baumannii Strains

2013 ◽  
Vol 58 (3) ◽  
pp. 1622-1629 ◽  
Author(s):  
Ramamourthy Gopal ◽  
Young Gwon Kim ◽  
Jun Ho Lee ◽  
Seog Ki Lee ◽  
Jeong Don Chae ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Biofilm Formation ◽  
Synergistic Effects ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Antibacterial Effects ◽  
Content Type ◽  
Chimeric Peptides ◽  
Novel Antibiotics

ABSTRACTThe increasing prevalence of drug-resistant pathogens highlights the need to identify novel antibiotics. Here we investigated the efficacies of four new antimicrobial peptides (AMPs) for potential drug development. The antibacterial activities, synergistic effects, and antibiofilm properties of the four chimeric AMPs were tested againstAcinetobacter baumannii, an emerging Gram-negative, nosocomial, drug-resistant pathogen. NineteenA. baumanniistrains resistant to ampicillin, cefotaxime, ciprofloxacin, tobramycin, and erythromycin were isolated at a hospital from patients with cholelithiasis. All four peptides exhibited significant antibacterial effects (MIC = 3.12 to 12.5 μM) against all 19 strains, whereas five commercial antibiotics showed little or no activity against the same pathogens. An exception was polymyxin, which was effective against all of the strains tested. Each of the peptides showed synergy against one or more strains when administered in combination with cefotaxime, ciprofloxacin, or erythromycin. The peptides also exhibited an ability to prevent biofilm formation, which was not seen with cefotaxime, ciprofloxacin, or erythromycin, though polymyxin also inhibited biofilm formation. Indeed, when administered in combination with ciprofloxacin, the AMP HPMA exerted a potent synergistic effect againstA. baumanniibiofilm formation. Collectively, our findings indicate that the AMPs tested have no cytotoxicity but possess potent antibacterial and antibiofilm activities and may act synergistically with commercial antibiotics.

Management of Multidrug-Resistant Tuberculosis

2018 ◽  
Vol 39 (03) ◽  
pp. 310-324 ◽  
Author(s):  
Jose Caminero ◽  
Charles Daley
Keyword(s):  
Multidrug Resistant ◽  
New Drugs ◽  
World Health ◽  
Drug Resistant ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Resistant Strains ◽  
Health Organization ◽  
Drug Resistant Strains

AbstractDrug-resistant strains of Mycobacterium tuberculosis pose a major threat to global tuberculosis control. Despite the availability of curative antituberculosis therapy for nearly half a century, inappropriate and inadequate treatment of tuberculosis, as well as unchecked transmission of M. tuberculosis, has resulted in alarming levels of drug-resistant tuberculosis. The World Health Organization (WHO) estimates that there were 600,000 cases of multidrug-resistant tuberculosis (MDR-TB)/rifampin-resistant (RR) tuberculosis in 2016, defined as strains that are resistant to at least isoniazid and rifampicin. Globally, WHO estimates that 4.1% of new tuberculosis cases and 19% of retreatment cases have MDR-TB. By the end of 2016, 123 countries had reported at least one case of extensively drug-resistant strains, which are MDR-TB strains that have acquired additional resistance to fluoroquinolones and at least one second-line injectable. It is estimated that only 22% of all MDR-TB cases are currently receiving therapy. This article reviews the management of MDR/RR-TB and updates recommendations regarding the use of shorter course regimens and new drugs.

scholarly journals Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide during 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Mariana Castanheira ◽  
Michael D. Huband ◽  
Rodrigo E. Mendes ◽  
Robert K. Flamm
Keyword(s):  
The United States ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Asia Pacific ◽  
Drug Resistant ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Extensively Drug Resistant ◽  
Encoding Genes

ABSTRACT We evaluated the activity of meropenem-vaborbactam against contemporary nonfastidious Gram-negative clinical isolates, including Enterobacteriaceae isolates with resistance phenotypes and carbapenemase genotypes. Meropenem-vaborbactam (inhibitor at 8 μg/ml) and comparators were susceptibility tested by reference broth microdilution methods against 14,304 Gram-negative clinical isolates collected worldwide during 2014. Carbapenemase-encoding genes were screened by PCR and sequencing. Meropenem-vaborbactam (MIC50/90, ≤0.015/0.06 μg/ml) inhibited 99.1 and 99.3% of the 10,426 Enterobacteriaceae isolates tested at ≤1 and ≤2 μg/ml, respectively. Meropenem inhibited 97.3 and 97.7% of these isolates at the same concentrations. Against Enterobacteriaceae isolates displaying carbapenem-resistant Enterobacteriaceae (CRE) (n = 265), multidrug-resistant (MDR) (n = 1,210), and extensively drug-resistant (XDR) (n = 161) phenotypes, meropenem-vaborbactam displayed MIC50/90 values of 0.5/32, 0.03/1, and 0.5/32 μg/ml, respectively, whereas meropenem activities were 16/>32, 0.06/32, and 0.5/32 μg/ml, respectively. Among all geographic regions, the highest meropenem-vaborbactam activities were observed for CRE and MDR isolates from the United States (MIC50/90, 0.03/1 and 0.03/0.12 μg/ml, respectively). Meropenem-vaborbactam was very active against 135 KPC producers, and all isolates were inhibited by concentrations of ≤8 μg/ml (133 isolates by concentrations of ≤2 μg/ml). This combination had limited activity against isolates producing metallo-β-lactamases (including 25 NDM-1 and 16 VIM producers) and/or oxacillinases (27 OXA-48/OXA-163 producers) that were detected mainly in Asia-Pacific and some European countries. The activity of meropenem-vaborbactam was similar to that of meropenem alone against Pseudomonas aeruginosa, Acinetobacter spp., and Stenotrophomonas maltophilia. Meropenem-vaborbactam was active against contemporary Enterobacteriaceae isolates collected worldwide, and this combination demonstrated enhanced activity compared to those of meropenem and most comparator agents against CRE isolates and KPC producers, the latter of which are often MDR.

scholarly journals World Health Organization reports highest rates of drug-resistant tuberculosis to date

2008 ◽  
Vol 13 (12) ◽  
pp. 11-12 ◽  
Author(s):  
Collective Editorial team
Keyword(s):  
Drug Resistance ◽  
World Health Organization ◽  
Multidrug Resistant ◽  
World Health ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Fourth Report ◽  
The World ◽  
Health Organization

On 26 February 2008, the World Health Organization (WHO) published its fourth report on the global situation regarding drug resistance in tuberculosis (TB). The report, based on information collected between 2002 and 2006 on 90,000 TB patients in 81 countries, found that 5.3% of the nine million new cases of TB each year are multidrug-resistant (MDR). This is the highest rate yet recorded.

Is effective patient support missing in the global response to multidrug-resistant tuberculosis?

2020 ◽  
Vol 24 (6) ◽  
pp. 626-630
Author(s):  
A. M. Cocozza ◽  
N. N. Linh ◽  
E. Jaramillo
Keyword(s):  
Treatment Outcomes ◽  
Multidrug Resistant ◽  
World Health ◽  
Drug Resistant ◽  
Patient Support ◽  
Global Response ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Health Organization

Multidrug-resistant tuberculosis (MDR-TB) is a threat to the achievement of the global targets to the World Health Organization (WHO) End TB by 2030 Strategy. The WHO consolidated guidelines for the treatment of drug-resistant TB emphasise the importance of addressing health systems issues, including supporting patients during treatment, contributing to improved adherence, reduced catastrophic costs and better treatment outcomes. The recently published results of the STREAM (Standardised Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) clinical trial and the Delamanid 213 Trial suggest that the implementation of a proper patient-centred approach to the clinical and programmatic management of MDR-TB as per the WHO guidelines is key to improving treatment outcomes in MDR-TB patients.

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