Extreme Antimicrobial Peptide and Polymyxin B Resistance in the Genus Burkholderia

Abstract

Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance.

Fosmidomycin Decreases Membrane Hopanoids and Potentiates the Effects of Colistin on Burkholderia multivorans Clinical Isolates

“…B. multivorans is highly resistant to both fosmidomycin and polymyxins (5,26). To determine if the growth of B. multivorans can be synergistically inhibited by treatment with a combination of colistin and fosmidomycin, initial MIC checker- To determine if the potentiating effect of fosmidomycin was specific for colistin, other antimicrobial classes that perturb the bacterial membrane were tested in concert with fosmidomycin for inhibition of B. multivorans growth ( Table 1).…”

“…Bcc bacteria are ominous CF pathogens because of their potential to cause rapid clinical deterioration and death (3). The major challenge to clinical therapy of Bcc pulmonary infections is their innate resistance to a broad range of antimicrobials, including polycationic agents that are typically used to treat other CF pulmonary pathogens (5). Although Burkholderia cenocepacia has widely been considered the most prevalent and virulent Bcc species in CF infections, the proportion of B. multivorans infections is increasing (6), with its incidence in CF patients now exceeding that of B. cenocepacia in the United States and Canada (7,8).…”

Candidate Essential Genes in Burkholderia cenocepacia J2315 Identified by Genome-Wide TraDIS

“…The Ara4N modification of lipid A is a regulated mechanism exploited by many Gram negative bacteria to resist cationic antimicrobial peptide, and under most growth conditions this modification is dispensable (Kawasaki et al, 2005; Lewenza et al, 2005; Loutet and Valvano, 2011; Lin et al, 2014). Hamad et al (2012) demonstrated that Ara4N served as a recognition signal for the transport of LPS to the outer membrane through the Lpt pathway, consolidating the essential role of this aminoarabinose in determining the architecture of the outer membrane in B. cenocepacia .…”

Bacterial Evasion of Host Antimicrobial Peptide Defenses

“…Burkholderia spp. are human pathogens associated with opportunistic infections in cystic fibrosis patients and chronic granulomatous disease (230). The high level AMP resistance exhibited by this Genus has been attributed to the constitutive incorporation of L -Ara4N into the LPS molecule (230, 231).…”

“…are human pathogens associated with opportunistic infections in cystic fibrosis patients and chronic granulomatous disease (230). The high level AMP resistance exhibited by this Genus has been attributed to the constitutive incorporation of L -Ara4N into the LPS molecule (230, 231). Alternative sigma factor RpoE coordinates Burkholderia gene expression under stress conditions and contributes to AMP resistance in a temperature-dependent manner (230, 232).…”