In-vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents

Díaz, María Carmen López; Ríos, Esther; Rodríguez-Avial, Iciar; Simaluiza, Rosa Janneth; Picazo, Juan J.; Culebras, Esther

doi:10.1016/j.ijantimicag.2017.01.039

Cited by 29 publications

(11 citation statements)

References 25 publications

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“…Indeed, antimicrobial potency reinforced this observation, and previous studies have reported that plazomicin remains active against Staphylococcus aureus harboring AAC(6′)-Ie-APH(2′′)-Ia, consistent with the relatively high K m (Table 3). 20…”

Section: ■Discussionmentioning

confidence: 99%

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

et al. 2018

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Plazomicin is a next-generation, semisynthetic aminoglycoside antibiotic currently under development for the treatment of infections due to multidrug-resistant Enterobacteriaceae. The compound was designed by chemical modification of the natural product sisomicin to provide protection from common aminoglycoside modifying enzymes that chemically alter these drugs via N-acetylation, O-adenylylation, or O-phosphorylation. In this study, plazomicin was profiled against a panel of isogenic strains of Escherichia coli individually expressing twenty-one aminoglycoside resistance enzymes. Plazomicin retained antibacterial activity against 15 of the 17 modifying enzyme-expressing strains tested. Expression of only two of the modifying enzymes, aac(2')-Ia and aph(2″)-IVa, decreased plazomicin potency. On the other hand, expression of 16S rRNA ribosomal methyltransferases results in a complete lack of plazomicin potency. In vitro enzymatic assessment confirmed that AAC(2')-Ia and APH(2'')-IVa (aminoglycoside acetyltransferase, AAC; aminoglycoside phosphotransferase, APH) were able to utilize plazomicin as a substrate. AAC(2')-Ia and APH(2'')-IVa are limited in their distribution to Providencia stuartii and Enterococci, respectively. These data demonstrate that plazomicin is not modified by a broad spectrum of common aminoglycoside modifying enzymes including those commonly found in Enterobacteriaceae. However, plazomicin is inactive in the presence of 16S rRNA ribosomal methyltransferases, which should be monitored in future surveillance programs.

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Section: ■Discussionmentioning

confidence: 99%

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

et al. 2018

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“…Three of these enzymes, ANT(4=)Ia nucleotidyltransferase, bidomain AAC(6=)le-APH(2=)la acetyltransferase and phosphotransferase, and APH(3=)IIIa phosphotransferase, confer resistance to one or more aminoglycosides used in clinical practice, including gentamicin, tobramycin, and amikacin and are common among MRSA isolates, although their relative prevalence varies geographically (75). Due to structural differences, plazomicin, a nextgeneration synthetic aminoglycoside, retained in vitro activity against 55 MRSA isolates that expressed one or more aminoglycoside-modifying enzymes (76). Plazomicin is not protected against other mechanisms of resistance, including 16s rRNA methyltransferases that directly modify the aminoglycoside target site, but these enzymes have not been reported in S. aureus (77).…”

Section: Resistance To Aminoglycosidesmentioning

confidence: 99%

Antimicrobial Resistance in Methicillin-Resistant Staphylococcus aureus to Newer Antimicrobial Agents

Watkins

Holubar

David

2019

Antimicrob Agents Chemother

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Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.

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“…The activity against Pseudomonas is similar to or slightly lower than other aminoglycosides [ 68 ]. Plazomicin is also active against methicillin-susceptible and methicillin-resistant Staphylococcus aureus [ 68 , 69 ].…”

Section: A Brief History Of Aminoglycoside Antibioticsmentioning

confidence: 99%

Amikacin: Uses, Resistance, and Prospects for Inhibition

2017

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Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against these antibiotics is enzymatic modification by aminoglycoside-modifying enzymes that are divided into acetyl-transferases, phosphotransferases, and nucleotidyltransferases. To overcome this problem, new semisynthetic aminoglycosides were developed in the 70s. The most widely used semisynthetic aminoglycoside is amikacin, which is refractory to most aminoglycoside modifying enzymes. Amikacin was synthesized by acylation with the l-(−)-γ-amino-α-hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. The main amikacin resistance mechanism found in the clinics is acetylation by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib], an enzyme coded for by a gene found in integrons, transposons, plasmids, and chromosomes of Gram-negative bacteria. Numerous efforts are focused on finding strategies to neutralize the action of AAC(6′)-Ib and extend the useful life of amikacin. Small molecules as well as complexes ionophore-Zn+2 or Cu+2 were found to inhibit the acetylation reaction and induced phenotypic conversion to susceptibility in bacteria harboring the aac(6′)-Ib gene. A new semisynthetic aminoglycoside, plazomicin, is in advance stage of development and will contribute to renewed interest in this kind of antibiotics.

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In-vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents

Cited by 29 publications

References 25 publications

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes

Antimicrobial Resistance in Methicillin-Resistant Staphylococcus aureus to Newer Antimicrobial Agents

Amikacin: Uses, Resistance, and Prospects for Inhibition

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