Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis

Tacconelli, Evelina; Carrara, Elena; Savoldi, Alessia; Harbarth, Stéphan Juergen; Mendelson, Marc; Monnet, Dominique; Pulcini, Céline; Kahlmeter, Gunnar; Kluytmans, Jan; Carmeli, Yehuda; Ouellette, Marc; Outterson, Kevin; Patel, Jean B.; Cavaleri, Marco; Cox, Edward; Houchens, Chris R; Grayson, M Lindsay; Hansen, Paul; Singh, Nalini; Theuretzbacher, Ursula; Magrini, Nicola; Aboderin, Aaron O.; Al-Abri, Seif; Jalil, Nordiah Awang; Benzonana, Nur; Bhattacharya, Sanjay; Brink, Adrian; Burkert, Francesco Robert; Cars, Otto; Cornaglia, Giuseppe; Dyar, Oliver James; Friedrich, Alex; Gales, Ana Cristina; Gandra, Sumanth; Giske, Christian G.; Goff, Debra A.; Goossens, Herman; Gottlieb, Thomas; Blanco, Manuel Guzmán; Hryniewicz, Waleria; Kattula, Deepthi; Jinks, T; Kanj, Souha S.; Kerr, Lawrence D.; Kiény, Marie-Paule; Kim, Yang Soo; Kozlov, Roman; Labarca, Jaime; Laxminarayan, Ramanan; Leder, Karin; Leibovici, Leonard; Levy-Hara, Gabriel; Littman, Jasper; Malhotra-Kumar, Surbhi; Manchanda, Vikas; Moja, Lorenzo; Ndoye, B; Pan, Angelo; Paterson, David L.; Paul, Mical; Qiu, Haibo; Ramón-Pardo, Pilar; Rodríguez-Baño, Jesús; Sanguinetti, Maurizio; Sengupta, Shamik; Sharland, Mike; Si-Mehand, Massinissa; Silver, Lynn L.; Song, Wonkeung; Steinbakk, Martin; Thomsen, Jens; Thwaites, Guy; Meer, J W van der; Kính, Nguyễn Văn; Vega, Silvio; Villegas, María Virginia; Wechsler-Fördös, Agnes; Wertheim, Heiman; Wesangula, Evelyn; Woodford, Neil; Yilmaz, Fidan O; Zorzet, Anna

doi:10.1016/s1473-3099(17)30753-3

Cited by 4,564 publications

(3,276 citation statements)

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“…Separating the transposase and transposon increased the efficiency of insertion sequencing and mapping, relative to the more common system of a single plasmid carrying both the transposase and the transposon, which resulted in a high percentage of reads that did not map to the recipient genome due to a second transposon in the donor plasmid which inserted itself with high frequency in the donor E. coli strain. Using tripartite matings, we obtained at least 5x10 6 distinct mutants for each strain from at least two independent conjugations, and selected mutants on each of five different agar media directly to avoid a bottleneck from pre-selecting the libraries on a given medium. A total of 1x10 6 mutants were selected on each medium in duplicate, yielding approximately a 10:1 mutant:TA insertion-site ratio, thus ensuring saturating mutagenesis.…”

Section: Resultsmentioning

confidence: 99%

Defining the core essential genome ofPseudomonas aeruginosa

Poulsen

Yang

Clatworthy

et al. 2018

Preprint

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Pseudomonas aeruginosa is a clinically significant pathogen that has alarming antibiotic resistance rates and very few candidate drugs in development. The challenges of novel drug discovery are exacerbated by incomplete knowledge of the essential genes across the species required for survival under infection conditions. We thus sought to define the core essential genome of P. aeruginosa by performing transposon insertion sequencing (Tn-Seq) on nine strains of P. aeruginosa isolated from different infection sites including wound, eye, lung, urinary tract, and blood, with an environmentally isolated strain for comparison, in five different media conditions: three were infection relevant media (serum, sputum, urine) and two were lab-based media (LB and M9 minimal). We developed a novel statistical model, FiTnEss, to classify genes as essential versus nonessential across all strain-media combinations. FiTnEss required minimal assumptions and had good predictive power in a limited set of validation studies with mutant strains of PA14 containing clean gene deletions. A core set of 321 essential genes emerged that are the highest probability targets for successful novel drug discovery against this important pathogen.

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Section: Resultsmentioning

confidence: 99%

Defining the core essential genome ofPseudomonas aeruginosa

Poulsen

Yang

Clatworthy

et al. 2018

Preprint

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“…Similar to RMP, liver injury is mediated by a toxic reactive intermediate, acetylhydrazine. Resistance to INH occurs frequently and requires its combination with RMP (RMP-INH) [123]. Single treatment of IND causes liver injury, which occurs much later than single treatment of RMP.…”

Section: Rifampin and Isoniazid Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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“…Several factors were considered in the creation of this list, including mortality, healthcare load, community charge, the prevalence of resistance, the 10-year tendency of resistance, transmission, prevention in the community, prevention in healthcare institutions, the ability to treat, and the pipeline. This priority list included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, as well as third-generation cephalosporin-and carbapenemresistant Enterobacteriaceae [12]. In relation to Gram-positive bacteria, vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus were also present [12].…”

mentioning

confidence: 99%

“…This priority list included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, as well as third-generation cephalosporin-and carbapenemresistant Enterobacteriaceae [12]. In relation to Gram-positive bacteria, vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus were also present [12]. Pathogens that cause community-acquired infections, such as clarithromycin-resistant Helicobacter pylori and fluoroquinolone-resistant Campylobacter spp., Neisseria gonorrhoeae and Salmonella typhi, were also included [12].…”

mentioning

confidence: 99%

“…In relation to Gram-positive bacteria, vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus were also present [12]. Pathogens that cause community-acquired infections, such as clarithromycin-resistant Helicobacter pylori and fluoroquinolone-resistant Campylobacter spp., Neisseria gonorrhoeae and Salmonella typhi, were also included [12].…”

mentioning

confidence: 99%

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