Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index

Mishra, Nigam M.; Stolarzewicz, I.; Cannaerts, David; Schuermans, J; Lavigne, Rob; Looz, Yannick; Landuyt, Bart; Schoofs, Liliane; Schols, Dominique; Paeshuyse, Jan; Hickenbotham, Peter; Clokie, Martha R. J.; Luyten, Walter; Eycken, Erik V. Van der; Briers, Yves

doi:10.3389/fmicb.2018.01175

Cited by 11 publications

(13 citation statements)

References 27 publications

(31 reference statements)

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“…Bactericidal activity was defined as a decrease of Ն3 log 10 CFU/ml relative to the initial inoculum. The time-kill curve data were, in every case, provided as arithmetic means and standard deviations from the results of at least 3 independent experiments, exactly according to standard time-kill methodology (17,(62)(63)(64)(65)(66)(67). For analyses in serum, blood, and plasma, all replicates were performed using the indicated number (n Ͼ 3) of biologically independent samples representing different lot numbers (Tables 1 and 2); thus, if 5 biologically independent replicates are indicated, the analysis was performed in the blood, sera, or plasma of 5 different individuals and/or pooled samples.…”

Section: Methodsmentioning

confidence: 99%

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

Sauve

Raz

Abdelhady

et al. 2019

Antimicrob Agents Chemother

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Bacteriophage-derived lysins are cell-wall-hydrolytic enzymes that represent a potential new class of antibacterial therapeutics in development to address burgeoning antimicrobial resistance. CF-301, the lead compound in this class, is in clinical development as an adjunctive treatment to potentially improve clinical cure rates of Staphylococcus aureus bacteremia and infective endocarditis (IE) when used in addition to antibiotics. In order to profile the activity of CF-301 in a clinically relevant milieu, we assessed its in vitro activity in human blood versus in a conventional testing medium (cation-adjusted Mueller-Hinton broth [caMHB]). CF-301 exhibited substantially greater potency (32 to Ն100-fold) in human blood versus caMHB in three standard microbiologic testing formats (e.g., broth dilution MICs, checkerboard synergy, and time-kill assays). We demonstrated that CF-301 acted synergistically with two key human blood factors, human serum lysozyme (HuLYZ) and human serum albumin (HSA), which normally have no nascent antistaphylococcal activity, against a prototypic methicillin-resistant S. aureus (MRSA) strain (MW2). Similar in vitro enhancement of CF-301 activity was also observed in rabbit, horse, and dog (but not rat or mouse) blood. Two well-established MRSA IE models in rabbit and rat were used to validate these findings in vivo by demonstrating comparable synergistic efficacy with standard-of-care anti-MRSA antibiotics at Ͼ100-fold lower lysin doses in the rabbit than in the rat model. The unique properties of CF-301 that enable bactericidal potentiation of antimicrobial activity via activation of "latent" host factors in human blood may have important therapeutic implications for durable improvements in clinical outcomes of serious antibiotic-resistant staphylococcal infections.

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Section: Methodsmentioning

confidence: 99%

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

Sauve

Raz

Abdelhady

et al. 2019

Antimicrob Agents Chemother

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“…E. faecium can acquire genes through mobile genetic elements such as plasmids and transposons (i.e vancomycin resistance can be transferred by the vanA gene cluster on the transposon Tn1546) [106]. Vancomycin acts by targeting the D-alanyl-D-alanine terminus of peptidoglycan inhibiting cell wall synthesis [107]. Vancomycin-resistance is mediated by several van gene clusters such as vanR, vanS, vanH, vanX and vanZ that are responsible for the replacement of D-Ala-D-Ala with D-alanyl-D-lactate termini.…”

Section: Enterococcimentioning

confidence: 99%

Bacterial Antibiotic Resistance: The Most Critical Pathogens

et al. 2021

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Antibiotics have made it possible to treat bacterial infections such as meningitis and bacteraemia that, prior to their introduction, were untreatable and consequently fatal. Unfortunately, in recent decades overuse and misuse of antibiotics as well as social and economic factors have accelerated the spread of antibiotic-resistant bacteria, making drug treatment ineffective. Currently, at least 700,000 people worldwide die each year due to antimicrobial resistance (AMR). Without new and better treatments, the World Health Organization (WHO) predicts that this number could rise to 10 million by 2050, highlighting a health concern not of secondary importance. In February 2017, in light of increasing antibiotic resistance, the WHO published a list of pathogens that includes the pathogens designated by the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) to which were given the highest “priority status” since they represent the great threat to humans. Understanding the resistance mechanisms of these bacteria is a key step in the development of new antimicrobial drugs to tackle drug-resistant bacteria. In this review, both the mode of action and the mechanisms of resistance of commonly used antimicrobials will be examined. It also discusses the current state of AMR in the most critical resistant bacteria as determined by the WHO’s global priority pathogens list.

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“…Another solution consists of modifying certain sites of the glycopeptides in order to improve their effectiveness or to extend their spectrum which can sometimes allow the molecule to acquire a new MoA [ 105 , 106 , 107 ]. This is, for example, the case for teicoplanin derivatives which show activity on both VRE VanB and VanA while teicoplanin has activity only on VanB strains [ 54 ].…”

Section: Alternatives To Vancomycinmentioning

confidence: 99%

Alternatives to Fight Vancomycin-Resistant Staphylococci and Enterococci

et al. 2021

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Gram positive pathogens are a significant cause of healthcare-associated infections, with Staphylococci and Enterococci being the most prevalent ones. Vancomycin, a last resort glycopeptide, is used to fight these bacteria but the emergence of resistance against this drug leaves some patients with few therapeutic options. To counter this issue, new generations of antibiotics have been developed but resistance has already been reported. In this article, we review the strategies in place or in development to counter vancomycin-resistant pathogens. First, an overview of traditional antimicrobials already on the market or in the preclinical or clinical pipeline used individually or in combination is summarized. The second part focuses on the non-traditional antimicrobials, such as antimicrobial peptides, bacteriophages and nanoparticles. The conclusion is that there is hitherto no substitute equivalent to vancomycin. However, promising strategies based on drugs with multiple mechanisms of action and treatments based on bacteriophages possibly combined with conventional antibiotics are hoped to provide treatment options for vancomycin-resistant Gram-positive pathogens.

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Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index

Cited by 11 publications

References 27 publications

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

The Antistaphylococcal Lysin, CF-301, Activates Key Host Factors in Human Blood To Potentiate Methicillin-ResistantStaphylococcus aureusBacteriolysis

Bacterial Antibiotic Resistance: The Most Critical Pathogens

Alternatives to Fight Vancomycin-Resistant Staphylococci and Enterococci

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