Antimicrobial activity of antisense peptide-peptide nucleic acid conjugates against non-typeable Haemophilus influenzae in planktonic and biofilm forms.
J Antimicrob Chemother
; 72(1): 137-144, 2017 01.
Article
em En
| MEDLINE
| ID: mdl-27986898
ABSTRACT
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 on media 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 µmol/L) for 20 clinical isolates, indicating susceptibility of planktonic NTHi. By contrast, MBECs were up to 179 mg/L (40 µmol/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 µmol/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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
/
4_TD
Base de dados:
MEDLINE
Assunto principal:
Proteína de Transporte de Acila
/
Haemophilus influenzae
/
Biofilmes
/
Oligodesoxirribonucleotídeos Antissenso
/
Ácidos Nucleicos Peptídicos
/
Antibacterianos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2017
Tipo de documento:
Article