A heterodimer comprised of two bovine lactoferrin antimicrobial peptides exhibits powerful bactericidal activity against Burkholderia pseudomallei

Abstract

Melioidosis is a severe infectious disease that is endemic in Southeast Asia and Northern Australia. Burkholderia pseudomallei, the causative agent of this disease, has developed resistance to an increasing list of antibiotics, demanding a search for novel agents. Lactoferricin and lactoferrampin are two antimicrobial domains of lactoferrin with a broad spectrum of antimicrobial activity. A hybrid peptide (LFchimera) containing lactoferrampin (LFampin265-284) and a part of lactoferricin (LFcin17-30) has strikingly higher antimicrobial activities compared to the individual peptides. In this study, the antimicrobial activities of this chimeric construct (LFchimera1), as well as of another one containing LFcin17-30 and LFampin268-284, a shorter fragment of LFampin265-284 (LFchimera2), and the constituent peptides were tested against 7 isolates of B. pseudomallei and compared to the preferential antibiotic ceftazidime (CAZ). All isolates including B. pseudomallei 979b shown to be resistant to CAZ, at a density of 10(5) CFU/ml, could be killed by 5-10 μM of LFchimera1 within 2 h, while the other peptides as well as the antibiotic CAZ only inhibited the B. pseudomallei strains resulting in an overgrowth in 24 h. These data indicate that LFchimera1 could be considered for development of therapeutic agents against B. pseudomallei.

Melioidosis: molecular aspects of pathogenesis

“…Mutations that disrupted LPS core biosynthesis and lipid A modifications, or compromised outer membrane integrity resulted in increased susceptibility of B. pseudomallei to CAPs and other antibiotics [113]. More recent studies, however, indicate that B. pseudomallei is highly susceptible to human cathelicidin peptide LL-37 and lactoferrin antimicrobial peptide derivatives, and that these may be useful in the development of novel therapeutic agents for treatment of melioidosis [115-117]. …”

Effects of lactoferrin derived peptides on simulants of biological warfare agents

“…Bactericidal effect was defined as a 10 log[reduction] > 3 in viability (Puknun et al 2013) ND not detected up to 50 μM peptide…”

“…The potency of this chimeric peptide provoked us to test the peptide against various human pathogens, like Staphylococcus aureus (Flores-Villasenor et al 2010) Escherichia coli O157:H7 (Flores-Villasenor et al 2012), Streptococcus pneumoniae Leon-Sicairos et al 2014) and Burkholderia pseudomallei (Kanthawong et al 2009; Puknun et al 2013, 2016), the latter which is classified by the Centers for Disease Control and Prevention as a category B biological warfare agent (BWA) (Rotz et al 2002). …”

Antimicrobial activity of Tachyplesin 1 againstBurkholderia pseudomallei: an in vitro and in silico approach

“…AMPs have made a big impact in antimicrobial research, to diminish the inefficacy of antimicrobial therapy in immunocompromised hosts and also ongoing emergence of resistance to conventional antibiotics worldwide (Giuliani, Pirri & Nicoletto, 2007). Among the AMPs which were reported to demonstrate potential to inhibit B. pseudomallei include LL-37 (Kanthawong et al, 2012), PG1 (Sim et al, 2011), bovine lactoferrin (Puknun et al, 2013), phospholipase A2 (Samy et al, 2015), and SMAP-29 (Blower, Barksdale & van Hoek, 2015). However, there are more potential AMPs that are yet to be tested against B. pseudomallei .…”

“…Groups of AMP’s i.e., defensins, cathelicidins, and dermicins have previously been reported to show potential against various pathogens (Wiesner & Vilcinskas, 2010). However, to date, only a few cathelicidin AMPs have been reported to be effective against B. pseudomallei, including LL-37 (Kanthawong et al, 2012), protegrin 1 (PG1) (Sim et al, 2011), bovine lactoferrin (Puknun et al, 2013), phospholipase A2 inhibitors (Samy et al, 2015), and sheep cathelicidin (SMAP-29) (Blower, Barksdale & van Hoek, 2015). …”