RT Journal Article
T1 Cooperative action of SP-A and its trimeric recombinant fragment with polymyxins against Gram-negative respiratory bacteria
A1 Coya, Juan Manuel
A1 Fraile Ágreda, Víctor
A1 Tapia, Lidia de
A1 García-Fojeda García-Valdecasas, María Belén
A1 Sáenz, Alejandra
A1 Bengoechea, José
A1 Kronqvist, Nina
A1 Johansson, Jan
A1 Casals Carro, María Cristina
AB The exploration of therapies combining antimicrobial lung proteins and conventional antibiotics is important due to the growing problem of multidrug-resistant bacteria. The aim of this study was to investigate whether human SP-A and a recombinant trimeric fragment (rfhSP-A) have cooperative antimicrobial activity with antibiotics against pathogenic Gram-negative bacteria. We found that SP-A bound the cationic peptide polymyxin B (PMB) with an apparent dissociation constant (KD) of 0.32 ± 0.04 µM. SP-A showed synergistic microbicidal activity with polymyxin B and E, but not with other antibiotics, against three SP-A-resistant pathogenic bacteria:Klebsiella pneumoniae, non-typable Haemophilus influenzae (NTHi), and Pseudomonas aeruginosa. SP-A was not able to bind toK. pneumoniae, NTHi, or to mutant strains thereof expressing long-chain lipopolysaccharides (or lipooligosaccharides) and/or polysaccharide capsules. In the presence of PMB, SP-A induced the formation of SP-A/PMB aggregates that enhance PMB-induced bacterial membrane permeabilization. Furthermore, SP-A bound to a molecular derivative of PMB lacking the acyl chain (PMBN) with aKDof 0.26 ± 0.02 μM, forming SP-A/PMBN aggregates. PMBN has no bactericidal activity but can bind to the outer membrane of Gram-negative bacteria. Surprisingly, SP-A and PMBN showed synergistic bactericidal activity against Gram-negative bacteria. Unlike native supratrimeric SP-A, the trimeric rfhSP-A fragment had small but significant direct bactericidal activity against K. pneumoniae, NTHi, and P. aeruginosa. rfhSP-A did not bind to PMB under physiological conditions but acted additively with PMB and other antibiotics against these pathogenic bacteria. In summary, our results significantly improve our understanding of the antimicrobial actions of SP-A and its synergistic action with PMB. A peptide based on SP-A may aid the therapeutic use of PMB, a relatively cytotoxic antibiotic that is currently being reintroduced into clinics due to the global problem of antibiotic resistance.
PB Frontiers
SN 1664-3224
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/94515
UL https://hdl.handle.net/20.500.14352/94515
LA eng
NO Coya JM, Fraile-Ágreda V, de Tapia L, García-Fojeda B, Sáenz A, Bengoechea JA, Kronqvist N, Johansson J and Casals C (2022) Cooperative action of SP-A and its trimeric recombinant fragment with polymyxins against Gram-negative respiratory bacteria. Front. Immunol. 13:927017. doi: 10.3389/fimmu.2022.927017
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Swedish Research Council
NO Universidad Complutense de Madrid
NO Swedish Biotechnology and Biological Sciences Research Council
NO Swedish Medical Research Council
NO Comunidad de Madrid
DS Docta Complutense
RD 10 abr 2025