Antimicrobial Peptides and Cell-Penetrating Peptides for Treating Intracellular Bacterial Infections

Abstract

Bacterial infections caused by intracellular pathogens are difficult to control. Conventional antibiotic therapies are often ineffective, as high doses are needed to increase the number of antibiotics that will cross the host cell membrane to act on the intracellular bacterium. Moreover, higher doses of antibiotics may lead to elevated severe toxic effects against host cells. In this context, antimicrobial peptides (AMPs) and cell-penetrating peptides (CPPs) have shown great potential to treat such infections by acting directly on the intracellular pathogenic bacterium or performing the delivery of cargos with antibacterial activities. Therefore, in this mini-review, we cover the main AMPs and CPPs described to date, aiming at intracellular bacterial infection treatment. Moreover, we discuss some of the proposed mechanisms of action for these peptide classes and their conjugation with other antimicrobials.

Keywords: AMPs; CPPs; antimicrobial peptides; cell-penetrating peptides; intracellular bacteria.

Figure 1

Schematic representation of the mechanism involved in bacteria, AMPs, and CPPs internalization into macrophages. Free-floating bacteria can invade the host cell by zipper or trigger mechanisms. Once inside the host cell, intracellular bacteria can occupy both the cytosol and vacuoles. At their therapeutic dose, conventional antibiotics usually present low permeability, rendering the intracellular bacterial infection treatment ineffective. By contrast, increasing antibiotics’ concentration can favor their permeabilization across the host cell membrane to treat the infection. However, as a consequence, it can also trigger cell toxicity. AMPs and CPPs have been used as alternative therapies. These peptide classes can translocate through the host cell plasma membrane via endocytosis, phagocytosis and macropinocytosis. In some cases, CPPs can also form transient toroidal pores or interact with membrane receptors. Once inside the cell, AMPs usually trigger direct antibacterial activities, whereas CPPs have been commonly used in conjunction with PNA and cargos aiming at essential bacterial genes silencing or direct antibacterial activities, respectively. Figure created with BioRender.com.