Journal
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
Volume 72, Issue 1, Pages 137-144Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkw384
Keywords
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Funding
- National Institute on Deafness and Other Communications Disorders [R21DC012917]
- National Institute of Allergy and Infectious Diseases [R01AI19641]
- National Center for Advancing Translational Sciences [UL1TR001412]
- Uehara Memorial Foundation
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Background: Antisense peptide nucleic acids (PNAs) are synthetic polymers that mimic DNA/RNA and inhibit bacterial gene expression in a sequence-specific manner. Methods: To assess activity against non-typeable Haemophilus influenzae (NTHi), we designed six PNA-peptides that target acpP, encoding an acyl carrier protein. MICs and minimum biofilm eradication concentrations (MBECs) were determined. Resistant strains were selected by serial passages onmedia with a sub-MIC concentration of acpP-PNA. Results: The MICs of six acpP-PNA-peptides were 2.9-11 mg/L (0.63-2.5 mmol/L) for 20 clinical isolates, indicating susceptibility of planktonic NTHi. By contrast, MBECs were up to 179 mg/L (40 mmol/L). Compared with one original PNA-peptide (acpP-PNA1-3' N), an optimized PNA-peptide (acpP-PNA14-5' L) differs in PNA sequence and has a 5' membrane-penetrating peptide with a linker between the PNA and peptide. The optimized PNA-peptide had an MBEC ranging from 11 to 23 mg/L (2.5-5 mmol/L), indicating susceptibility. A resistant strain that was selected by the original acpP-PNA1-3' N had an SNP that introduced a stop codon in NTHI0044, which is predicted to encode an ATP-binding protein of a conserved ABC transporter. Deletion of NTHI0044 caused resistance to the original acpP-PNA1-3' N, but showed no effect on susceptibility to the optimized acpP-PNA14-5' L. The WT strain remained susceptible to the optimized PNA-peptide after 30 serial passages on media containing the optimized PNA-peptide. Conclusions: A PNA-peptide that targets acpP, has a 5' membrane-penetrating peptide and has a linker shows excellent activity against planktonic and biofilm NTHi and is associated with a low risk for induction of resistance.
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