Morpholino oligomers tested in vitro, in biofilm and in vivo against multidrug-resistant Klebsiella pneumoniae

Geller, Bruce L.; Li, Lixin; Martinez, Fabian G.; Sully, Erin K.; Sturge, Carolyn R.; Daly, Seth M.; Pybus, Christine; Greenberg, David E.

doi:10.1093/jac/dky058

Cited by 28 publications

(24 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For systemic diseases, CPP‐ONs circumvent cell‐specific receptors, allowing for pharmacological activity across multiple tissues, and they have been developed for uptake into particularly impervious tissues, e.g . skeletal muscle, heart and CNS (Hammond et al, 2016; Betts et al, 2019), as well as targeting viral and bacterial infections (Burrer et al, 2007; Geller et al, 2013; Geller et al, 2018). At the time of this review, a phase I clinical trial for safety and tolerability of an arginine‐rich CPP‐ASO conjugate for DMD (SRP‐5051) has been completed and a phase II is recruiting to determine the optimal dose.…”

Section: Introductionmentioning

confidence: 99%

Delivery of oligonucleotide‐based therapeutics: challenges and opportunities

et al. 2021

View full text Add to dashboard Cite

Nucleic acid‐based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid‐based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics.

show abstract

Section: Introductionmentioning

confidence: 99%

Delivery of oligonucleotide‐based therapeutics: challenges and opportunities

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Specifically, the (KFF) 3 K peptide conjugated to a PNA targeting the essential bacterial gene, acpP , was shown to be sequence specifically bactericidal against Escherichia coli (Good et al, 2001). Subsequently, antibacterial effects of peptide-PNA [and also of phosphordiamidate morpholino oligomer (PMO) (Geller et al, 2018)] conjugates against a range of antibiotic resistant bacterial species have been reported, e.g., multi-resistant Klebsiella pneumoniae (Kurupati et al, 2007) and Haemophilus influenzae (Otsuka et al, 2017), and Pseudomonas aeruginosa (Montagner et al, 2017) in planktonic cultures as well as biofilms. Furthermore, recent studies have identified the inner-membrane SbmA protein as a necessary transporter of some peptide-PNA conjugates (Ghosal et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

PNA Length Restriction of Antibacterial Activity of Peptide-PNA Conjugates in Escherichia coli Through Effects of the Inner Membrane

et al. 2019

View full text Add to dashboard Cite

Peptide Nucleic Acid (PNA)-peptide conjugates targeting essential bacterial genes are showing promise as antisense antimicrobials in drug discovery. Optimization has focused on selection of target genes and exact localization around the ribosome binding site, but surprisingly a length optimum around 10–12 nucleobases has been found. Addressing this observation, we have investigated the relationship between PNA-length, PNA–RNA duplex stability and antimicrobial activity in E. coli in more detail. For PNAs of identical length of ten nucleobases the expected reverse correlation between the thermal stability (Tm) of the PNA–RNA duplex and the MIC for single mismatched PNAs was found. Also the expected direct correlation between the length of the PNA and the PNA–RNA duplex stability was found. Nonetheless, 10-mer PNAs [in a 6–18 mer extension series of (KFF) 3 K- and (RXR) 4 conjugates] were the most active as antisense antimicrobials in both wild type E. coli MG1655 and AS19, suggesting that the size constraint is related to the bacterial uptake of PNA-peptide conjugates. This conclusion was supported by flow cytometry data showing higher bacterial uptake of shorter PNA fluorophore labeled conjugates. Interestingly, the size-limited uptake seems independent on outer membrane integrity (AS19), and thus the results suggest that the inner membrane limits the molecular size for peptide-PNA passage.

show abstract

“…As compiled in a recent excellent review by others (Sully & Geller, 2016), ASO-based antimicrobials have since been tested in vitro or in vivo in many more bacteria than E. coli. The published work spans Gram-negative Acinetobacter, Brucella, Burkholderia, Campylobacter, Haemophilus, Klebsiella, Pseudomonas, and Salmonella species, and Gram-positive Enterococcus, Listeria, Staphylococcus and Streptococcus species (Geller et al, 2018;Sully & Geller, 2016).…”

Section: Vogelmentioning

confidence: 99%

“…tions, suggesting that they may be therapeutically useful for treating sepsis or different diseases of the lung (Barkowsky et al, 2019;Daly et al, 2018;Geller et al, 2018;Sully & Geller, 2016).…”

Section: Asos Have Shown Efficacy In Different Experimental Mouse Infec-mentioning

confidence: 99%

“…As compiled in a recent excellent review by others (Sully & Geller, ), ASO‐based antimicrobials have since been tested in vitro or in vivo in many more bacteria than E. coli . The published work spans Gram‐negative Acinetobacter , Brucella, Burkholderia, Campylobacter, Haemophilus, Klebsiella, Pseudomonas, and Salmonella species, and Gram‐positive Enterococcus , Listeria, Staphylococcus and Streptococcus species (Geller et al, ; Sully & Geller, ). ASOs have shown efficacy in different experimental mouse infections, suggesting that they may be therapeutically useful for treating sepsis or different diseases of the lung (Barkowsky et al, ; Daly et al, ; Geller et al, ; Sully & Geller, ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An RNA biology perspective on species‐specific programmable RNA antibiotics

Vogel

2020

Molecular Microbiology

View full text Add to dashboard Cite

Our body is colonized by a vast array of bacteria the sum of which forms our microbiota. The gut alone harbors >1,000 bacterial species. An understanding of their individual or synergistic contributions to human health and disease demands means to interfere with their functions on the species level. Most of the currently available antibiotics are broad‐spectrum, thus too unspecific for a selective depletion of a single species of interest from the microbiota. Programmable RNA antibiotics in the form of short antisense oligonucleotides (ASOs) promise to achieve precision manipulation of bacterial communities. These ASOs are coupled to small peptides that carry them inside the bacteria to silence mRNAs of essential genes, for example, to target antibiotic‐resistant pathogens as an alternative to standard antibiotics. There is already proof‐of‐principle with diverse bacteria, but many open questions remain with respect to true species specificity, potential off‐targeting, choice of peptides for delivery, bacterial resistance mechanisms and the host response. While there is unlikely a one‐fits‐all solution for all microbiome species, I will discuss how recent progress in bacterial RNA biology may help to accelerate the development of programmable RNA antibiotics for microbiome editing and other applications.

show abstract

Morpholino oligomers tested in vitro, in biofilm and in vivo against multidrug-resistant Klebsiella pneumoniae

Cited by 28 publications

References 31 publications

Delivery of oligonucleotide‐based therapeutics: challenges and opportunities

Delivery of oligonucleotide‐based therapeutics: challenges and opportunities

PNA Length Restriction of Antibacterial Activity of Peptide-PNA Conjugates in Escherichia coli Through Effects of the Inner Membrane

An RNA biology perspective on species‐specific programmable RNA antibiotics

Contact Info

Product

Resources

About