Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent

Zhanel, George G.; Esquivel, Jenine; Zelenitsky, Sheryl; Lawrence, Courtney K.; Adam, Heather J.; Golden, Alyssa; Hink, Rachel; Berry, Liam; Schweizer, Frank; Zhanel, Michael A.; Bay, Denice C.; Lagacé-Wiens, Philippe; Walkty, Andrew; Lynch, Joseph P.; Karlowsky, James A.

doi:10.1007/s40265-020-01257-4

Cited by 71 publications

(64 citation statements)

References 78 publications

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“…β-lactamases with carbapenemase activity have been identified in both of these families including SBLs such as KPC and OXA-48-like, and the MBLs NDM, VIM and IMP (2). The recent introduction of serine carbapenemase inhibitors such as avibactam, vaborbactam and relebactam used in combination with β-lactams, have provided on September 1, 2020 by guest http://aac.asm.org/ Downloaded from treatment options against serine carbapenemase-producing Gram-negative pathogens (7,8).…”

Section: Introductionmentioning

confidence: 99%

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Samuelsen

Åstrand

Fröhlich

et al. 2020

Antimicrob Agents Chemother

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Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

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Section: Introductionmentioning

confidence: 99%

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Samuelsen

Åstrand

Fröhlich

et al. 2020

Antimicrob Agents Chemother

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“…They are teratogenic, and the anticoagulant dose needs adjustment when used concomitantly. A slightly increased mortality was observed in the CABP trial of omadacycline [94].…”

Section: Toxicity/adverse Effectsmentioning

confidence: 92%

“…Two other newer tetracycline derivatives have been released Eravacycline, a fluorocycline, and Omadacycline, an aminomethylcycline., while omadacycline has been approved for SSTI and CABP. In contrast, Eravacycline has been approved for cIAI [94,95]. Similar to tigecycline, neither of these agents cover pseudomonas.…”

Section: Toxicity/adverse Effectsmentioning

confidence: 99%

Bactericidal and Bacteriostatic Antibiotics

Patil¹,

Patel²

2021

Infections and Sepsis Development

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Of all the medications available to physicians worldwide, antibiotics play an essential role in inpatient and outpatient settings. Discovered in the early nineteenth century by Alexander Fleming, penicillin was the first antibiotic isolated from a mold. Dr. Gerhard Domagk developed synthetic sulfa drugs by altering the red dye used in chemical industries. Since then, multiple antibiotic classes have been discovered with varying antimicrobial effects enabling their use empirically or in specific clinical scenarios. Antibiotics with different mechanisms of action could be either bactericidal or bacteriostatic. However, no clinical significance has been observed between cidal and static antibiotics in multiple trials. Their presence has led to safer deep invasive surgeries, advanced chemotherapy in cancer, and organ transplantation. Indiscriminate usage of antibiotics has resulted in severe hospital-acquired infections, including nosocomial pneumonia, Clostridioides difficile infection, multidrug-resistant invasive bacterial infections, allergic reactions, and other significant side effects. Antibiotic stewardship is an essential process in the modern era to advocate judicial use of antibiotics for an appropriate duration. They play a vital role in medical and surgical intensive care units to address the various complications seen in these patients. Antibiotics are crucial in severe acute infections to improve overall mortality and morbidity.

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“…Omadacycline aminomethylcycline is a semisynthetic derivative of tetracycline, and it is active against many Gram-negative bacteria and Gram-positives, including MRSA, S. aureus , S. pneumoniae , β-hemolytic streptococci, Enterococcus VRE, and Enterobacteriaceae in vitro [ 393 ] and in vivo in clinical practice [ 394 ]. Similar activity has also been found in the thermostable antimicrobial peptide discovered in Hungary in Xenorhabdus budapestensis and X. szentirmaii [ 31 , 395 , 396 , 397 , 398 , 399 ] and later identified as fabclavine [ 400 , 401 , 402 , 403 , 404 , 405 ].…”

Section: The Efforts To Discover Omnipotent (“Jolly Joker”) Antibimentioning

confidence: 99%

Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

Fodor

Abate²,

Deák

et al. 2020

Pathogens

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Antibiotic poly-resistance (multidrug-, extreme-, and pan-drug resistance) is controlled by adaptive evolution. Darwinian and Lamarckian interpretations of resistance evolution are discussed. Arguments for, and against, pessimistic forecasts on a fatal “post-antibiotic era” are evaluated. In commensal niches, the appearance of a new antibiotic resistance often reduces fitness, but compensatory mutations may counteract this tendency. The appearance of new antibiotic resistance is frequently accompanied by a collateral sensitivity to other resistances. Organisms with an expanding open pan-genome, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, can withstand an increased number of resistances by exploiting their evolutionary plasticity and disseminating clonally or poly-clonally. Multidrug-resistant pathogen clones can become predominant under antibiotic stress conditions but, under the influence of negative frequency-dependent selection, are prevented from rising to dominance in a population in a commensal niche. Antimicrobial peptides have a great potential to combat multidrug resistance, since antibiotic-resistant bacteria have shown a high frequency of collateral sensitivity to antimicrobial peptides. In addition, the mobility patterns of antibiotic resistance, and antimicrobial peptide resistance, genes are completely different. The integron trade in commensal niches is fortunately limited by the species-specificity of resistance genes. Hence, we theorize that the suggested post-antibiotic era has not yet come, and indeed might never come.

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Omadacycline: A Novel Oral and Intravenous Aminomethylcycline Antibiotic Agent

Cited by 71 publications

References 78 publications

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Bactericidal and Bacteriostatic Antibiotics

Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review

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