Lactoferrin and Its Derived Peptides: An Alternative for Combating Virulence Mechanisms Developed by Pathogens

Abstract

Due to the emergence of multidrug-resistant pathogens, it is necessary to develop options to fight infections caused by these agents. Lactoferrin (Lf) is a cationic nonheme multifunctional glycoprotein of the innate immune system of mammals that provides numerous benefits. Lf is bacteriostatic and/or bactericidal, can stimulate cell proliferation and differentiation, facilitate iron absorption, improve neural development and cognition, promote bone growth, prevent cancer and exert anti-inflammatory and immunoregulatory effects. Lactoferrin is present in colostrum and milk and is also produced by the secondary granules of polymorphonuclear leukocytes, which store this glycoprotein and release it at sites of infection. Lf is also present in many fluids and exocrine secretions, on the surfaces of the digestive, respiratory and reproductive systems that are commonly exposed to pathogens. Apo-Lf (an iron-free molecule) can be microbiostatic due to its ability to capture ferric iron, blocking the availability of host iron to pathogens. However, apo-Lf is mostly microbicidal via its interaction with the microbial surface, causing membrane damage and altering its permeability function. Lf can inhibit viral entry by binding to cell receptors or viral particles. Lf is also able to counter different important mechanisms evolved by microbial pathogens to infect and invade the host, such as adherence, colonization, invasion, production of biofilms and production of virulence factors such as proteases and toxins. Lf can also cause mitochondrial and caspase-dependent regulated cell death and apoptosis-like in pathogenic yeasts. All of these mechanisms are important targets for treatment with Lf. Holo-Lf (the iron-saturated molecule) can contain up to two ferric ions and can also be microbicidal against some pathogens. On the other hand, lactoferricins (Lfcins) are peptides derived from the N-terminus of Lf that are produced by proteolysis with pepsin under acidic conditions, and they cause similar effects on pathogens to those caused by the parental Lf. Synthetic analog peptides comprising the N-terminus Lf region similarly exhibit potent antimicrobial properties. Importantly, there are no reported pathogens that are resistant to Lf and Lfcins; in addition, Lf and Lfcins have shown a synergistic effect with antimicrobial and antiviral drugs. Due to the Lf properties being microbiostatic, microbicidal, anti-inflammatory and an immune modulator, it represents an excellent natural alternative either alone or as adjuvant in the combat to antibiotic multidrug-resistant bacteria and other pathogens. This review aimed to evaluate the data that appeared in the literature about the effects of Lf and its derived peptides on pathogenic bacteria, protozoa, fungi and viruses and how Lf and Lfcins inhibit the mechanisms developed by these pathogens to cause disease.

Bovine apo-lactoferrin affects the secretion of proteases in Mannheimia haemolytica A2

“…Moreover, since M. haemolytica is involved in a multifactorial disease in which associated viruses are involved, Lf might also show antiviral properties in mannheimiosis. In other viruses, the antiviral properties are related to the ability of Lf to block the cellular attachment or replication of a virus by inducing type I interferons (α/β) with antiviral action [ 57 ].…”

Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by the N-terminal peptide of lactoferrin

“…According to mapping studies, LF binds to Plg via its highly cationic N-terminal region (7). From this region (residues 1-49), the biologically active natural peptides, called lactoferricins (LFCs), with antiviral and antibacterial activities are derived (8,9). Notably, synthetic analogs of LFCs possess antimicrobial properties similar to natural fragments (9).…”

“…From this region (residues 1-49), the biologically active natural peptides, called lactoferricins (LFCs), with antiviral and antibacterial activities are derived (8,9). Notably, synthetic analogs of LFCs possess antimicrobial properties similar to natural fragments (9). To specify the role of the N-terminal region in Plg inhibition, we tested the inhibitory capacity of the corresponding synthetic peptide pLF1.…”

Physicochemical Features and Peculiarities of Interaction of AMP with the Membrane

“…Antimicrobial peptides of the family of Lactoferricins that are known as Trp-rich peptides, show cell-permeable capabilities. Interacting with the membrane via electrostatic and/or hydrophobic interactions, they may form pores or inverted micelles to shuttle inside the cell [91]. Their mechanism to enter cells is similar to CPPs; once in the cell, they can interact with DNA or RNA, affecting their synthesis.…”