Antimicrobial peptides: the battle against multidrug resistant microbes

Antimicrobial peptides: the battle against multidrug resistant microbes

Antimicrobial peptides play a key role in the innate immunity of all living beings and are bringing new hope in the battle against the escalation of multidrug resistant microbes.

The Gomes team looks at new ways to make these peptides useful to fight infections. The Gomes Lab (see Fig. 1) is strongly motivated towards the development of peptide-based approaches against infectious diseases, from both the medicinal chemistry and the biomedical perspectives, for which it has established strong collaborations with groups having complementary skills while sharing this common interest. Peptide-based research by the Gomes team focuses on two main topics: peptide and peptidomimetic derivatives of antimalarial drugs and, more recently, antimicrobial peptides (AMP) and antimicrobial peptides-based materials and formulations for the management of bone and skin infections.

Antimicrobial peptides to improve antimalarial drug action

Rescuing classical antimalarial drugs is amongst the earliest research goals of the team, taking advantage of their long-lasting collaboration with reputed malaria experts from the Institute of Molecular Medicine and the Institute of Hygiene and Tropical Medicine, both in Lisbon, Portugal. The team believes drug rescuing is likely to deliver low cost medicines against malaria, which is endemic in low to middle income countries.

At Gomes’s lab, peptides have been linked to antimalarial drugs with a double purpose:
n Small peptides and peptidomimetics have been used as ‘masks’ to avoid premature degradation of the drugs in the body, while preserving their activity.

Cell penetrating peptides (CPP) are being investigated both for the aforementioned purpose, and as ‘shuttles’ to improve intracellular drug delivery.

This line of work was funded through the Portuguese national funding agency for science, research and technology (FCT) grants PTDC/QUI/65142/2006 and PTDC/QUI-QUI/116864/2010, both of which have Paula Gomes as the Principal Investigator (PI).
This line of research has been delivering, since 2005, metabolically-stable peptidomimetic derivatives of antimalarials that were able to block malaria transmission in animals, and the recent discovery of CPP-drug conjugates with improved activity against liver-stage malaria, as compared to the unconjugated drug.1

Antimicrobial peptides as key players in the management of bone, skin, and soft tissue infections

The increased life expectancy and lifestyle that characterise the so-called developed countries are having a direct and indirect impact on the rise of multidrug resistant bacterial infections, namely, due to:

  • Widespread abuse of antibiotics prescriptions feeding the continuous expansion of multidrug resistant pathogens;
  • Exponential increase in the number of orthopaedic implants on elderly people, with a considerable risk of nosocomial infections installing at the implantation site; and
  • Chronically-infected wounds such as pressure ulcers, venous leg ulcers, and diabetic foot ulcers (DFU), all of which more common in elderly and/or overweighed, diabetic people.

Conscious of the potential of AMP to tackle the serious health threat posed by multidrug resistant infections, the Gomes’s team has partnered with experts in Biomedical Engineering and in Biological Sciences, to explore new AMP-based strategies for applications that span from management of bone (osteomyelitis) and skin and soft tissue infections (SSTI), to development of antibacterial casings for processed foods.

Antimicrobial coatings for biomedical engineering and the agro-food industry

At Gomes’s lab, both new synthetic AMP2 and chemical strategies for the controlled attachment of selected AMP onto chitosan surfaces3,4 are being developed with the purpose to create antibacterial coatings, in close collaboration with Cristina Martins, leader of the Bioengineered Surfaces group at the Institute of Biomedical Engineering of the University of Porto.

This research has been steadily receiving support from FCT, earlier through grant PTDC/CTM/101484/2008 given to the project ‘CHITOSAMP’ (Gomes as the PI) focused on antibacterial coatings for bone implants, and more recently through grant POCI-01-0145-FEDER-031781 given to project ‘ANTINFECT’ (Martins as the PI), targeted at antibacterial wound dressings. While the latter project is at its very onset, ‘CHITOSAMP’ has already conveyed important advances in the development of coatings with antibacterial activity, due to either ‘bacteria repelling effects’ (decreased bacterial adhesion onto the coated surfaces) or bactericidal action, depending on procedures employed to prepare both the AMP-chitosan coatings and the coated surfaces.3-5

An identical concept is now being applied at the Gomes’s Lab with a completely different purpose, by Gomes’s Research Associate Cátia Teixeira; this researcher was recently awarded grant POCI-01-0145-FEDER-31798, co-funded by FEDER and FCT, to develop AMP-modified casings for ‘alheira’, a typical sausage from the Northeast of Portugal.
Using ionic liquids to enhance skin permeation of AMP for topical wound care
Over 50% of chronically-infected wounds are associated with localised bacterial biofilms causing severe infections that contribute to tissue destruction, delayed wound healing, and impairment of good health and wellbeing.

Topical application of natural or synthetic AMP on the chronic wound may overcome this barrier, as many AMP display wound-healing properties, by promoting cell migration and proliferation in the healing process (see Fig. 2).

Gomes’ team, in collaboration with experts from the Health School of the Polytechnic of Porto, is launching a new project where ionic liquids are being explored as a means to enhance skin permeation of AMP, towards the development of novel topical formulations for wound care. The exploratory phase of this emerging project is being partially funded through the Norte Portugal Regional Coordination and Development Commission (CCDR-N) grant DESignBIOtechHealth (Norte-01-0145-FEDER-000024).

This work was financed by Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020 – Operacional Programme for Competitiveness and Internationalisation (POCI), and by Portuguese funds through FCT – Fundação para a Ciência e a Tecnologia in the framework of the project POCI-01-0145-FEDER-31798
References

1 L. Aguiar et al. ‘Coupling the cell penetrating peptides Transportan and Transportan-10 to primaquine enhances its activity against liver stage malaria parasites’. Medicinal Chemistry Communications 2018, ahead-of-print (DOI: 10.1039/C8MD00447A)
2 C. Monteiro et al. ‘A 17-mer membrane-active MSI-78 derivative with improved selectivity towards bacterial cells’. Molecular Pharmaceutics 2015, 12, 2904-2911 (DOI: 10.1021/acs.molpharmaceut.5b00113)
3 F. Costa et al. ‘Dhvar5 antimicrobial peptide (AMP) chemoselective covalent immobilization results on higher antiadherence effect than simple physical adsorption’. Biomaterials 2015, 52, 531-538 (DOI: 10.1016/j.biomaterials.2015.02.049)
4 M. Barbosa et al. ‘Tethering antimicrobial peptides onto chitosan: optimization of azide-alkyne ‘click’ reaction conditions’. Carbohydrate Polymers 2017, 165, 384-393 (DOI: 10.1016/j.carbpol.2017.02.050)
5 M. Barbosa et al. ‘Antimicrobial coatings prepared from Dhvar-5 click-grafted chitosan powders’. Acta Biomaterialia 2018 (just accepted)

Paula Gomes
Associate Professor
FCUP
Senior Researcher
LAQV-REQUIMTE
+351 933202430
pgomes@fc.up.pt
Tweet @UPorto
www.fc.up.pt/pessoas/pgomes/

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