Vibrio cholerae amino acids go on the defense

Abstract

Edited by Chris WhitfieldGram-negative bacteria remodel their surfaces to interact with the environment, particularly to protect pathogens from immune surveillance and host defenses. The enzyme AlmG is known to be involved in remodeling the Vibrio cholerae surface, but its specific role was not clear. A new study characterizes AlmG at the molecular level, showing it defies phylogenetic expectations to add amino acids to lipopolysaccharide (LPS). This LPS modification plays a pivotal role in V. cholerae resistance to antimicrobial peptides, weapons of the innate immune system against infections.A defining feature of Gram-negative bacteria is the presence of an outer membrane, which is an asymmetrical bilayer with glycerophospholipids on the cytoplasmic face and LPS 2 anchored to the outer face. The LPS is composed of three regions: the lipid A domain, the core oligosaccharide, and the O-antigen polysaccharide. The lipid A domain is recognized by the innate immune system, leading to the activation of signaling pathways governing host-defense responses, and is the target of antimicrobial peptides such as defensins and polymyxin B, which kill bacteria by affecting membrane integrity. Recognition and exploitation of the lipid A structure therefore relies on the inability of bacteria to alter this component dramatically. However, a wealth of evidence demonstrates that bacteria do modify their lipid A as a virulence strategy to survive the onslaught of host defenses. The canonical lipid A structure, lipid IV A , is found in Escherichia coli K-12 and consists of a glucosamine disaccharide modified with two phosphate groups and four R-3-hydroxymyristoyl acyl chains. Two of the hydroxymyristoyl chains are further acylated with laureate (containing a C 12 backbone) and myristate (C 14 ) through the action of the late acyltransferases LpxL and LpxM, respectively (1). Pioneering studies demonstrated that Salmonella typhimurium remodels its lipid A by adding 4-amino-4-deoxy-L-arabinose and phosphoethanolamine to mask lipid A's negative charges, limiting its interaction with positively-charged antimicrobial peptides (2, 3), whereas Klebsiella pneumoniae produces a distinct lipid A in vivo to limit inflammation and to resist antimicrobial peptides and polymyxins (4). Although these remodeling events are therefore critical to understanding a variety of bacterial infections, most of the studies on lipid A remodeling have focused primarily on just a few bacterial species.V. cholerae is the causative agent responsible for the severe diarrheal disease cholera. The global disease burden of cholera is estimated to be between 1.3 and 4 million cases per year with 21,000 to 143,000 deaths. For decades, this pathogen has been used as a model to study the regulation of host-pathogen interactions and, more recently, has enabled investigations of the type VI secretion system that facilitates direct killing of competitors. However, until recently, there was a major gap in our understanding of V. cholerae LPS and its contribution to virulence...

Action and mechanism of the colistin resistance enzyme MCR-4

“…This dampens the net negative charge and consequently reduces the affinity of colistin. Obviously, it is distinct from other known mechanisms for colistin resistance, like the addition of 4-amino-4-deoxy-L-arabinose to lipid A in Salmonella enterica 12,13 and Pseudomonas aeruginosa 14 and the glycine/diglycine modification of lipid A in Vibrio cholerae biotype EI Tor 15–18 . Unlike natural/intrinsic polymyxin resistance which is limited to clonal expansion, the horizontal transfer of mcr-1 -mediated colistin resistance is rapid and can disseminate across different bacterial species.…”

Antibiotic Susceptibility Testing (AST) Reports: A Basis for Environmental/Epidemiological Surveillance and Infection Control Amongst Environmental Vibrio cholerae

“…Other studies also added that antibiotic resistance resulted as survival mechanism of various Gram-negative pathogens due to inappropriate usage and use of antibiotics as therapeutic prophylactics against pathogens [ 6 , 7 ]. The organisms in such an environment thereafter muster survival strategies, using developed immunity [ 8 , 9 , 10 ], multiple antibiotic resistance (MAR) [ 11 , 12 , 13 , 14 , 15 , 16 ], multiple patho-genetically diverse genes [ 4 , 17 , 18 , 19 , 20 ], multiple biochemical pathways [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ] and multiple epidemiological (pandemic/epidemic) variants virulent determinants [ 18 , 19 ]. In the environment, various antimicrobial/chemical agents have been released as waste and/or applied either to kill or reduce the quantity of bacterial (as bacteriocides) in both terrestrial and aquaculture [ 28 ] which have also encouraged development of multiple antibiotic resistance (MAR) amongst halophilic pathogens such as V. cholerae [ 29 ].…”

“…Such antibiotic resistances amongst environmental bacterial specie pose threats to both humans and the environment as there is possibility of transfer or sharing of multiple drug resistant genes amongst potential pathogens via horizontal gene transfer [ 6 ]. Other recent studies conducted by various investigators have affirmed that V. cholerae thrive in the environment, remodel its surface lipopolysaccharide (LPS) and protect itself from host defenses, drug agents and immune scrutiny [ 15 ]. One surface enzyme expressed by members of V. cholerae with such character is the AlmG which plays a pivotal role in peptide-bound antibiotic resistance and survival against host defense [ 13 , 15 ].…”

“…Other recent studies conducted by various investigators have affirmed that V. cholerae thrive in the environment, remodel its surface lipopolysaccharide (LPS) and protect itself from host defenses, drug agents and immune scrutiny [ 15 ]. One surface enzyme expressed by members of V. cholerae with such character is the AlmG which plays a pivotal role in peptide-bound antibiotic resistance and survival against host defense [ 13 , 15 ]. Numerous studies have associated resistance to peptide-bound antibiotics with phosphoethanolamine modification of lipid A [ 13 ] which is common amongst the El Tor V. cholerae strains.…”

Spread of MCR-3 Colistin Resistance in China: An Epidemiological, Genomic and Mechanistic Study

“…The chemical mechanism underlying the colistin resistance consistently involves bacterial lipid A-centered surface remodeling, including i) The addition of 4-amino-4-deoxy-L-arabinose in S . enterica [ 16 , 17 ] and Pseudomonas aeruginosa [ 18 ]; ii) The attachment of p hospho e thanol a mine (PEA) in Neisseria [ 19 ], Acinetobacter baumannii [ 20 ] and Campylobacter jejuni [ 21 ]; and iii) Glycine/diglycine modification in the pandemic Vibrio cholerae biotype EI Tor [ [22] , [23] , [24] , [25] ]. Intrinsic resistance to polymyxin is limited to the originally-resistant population.…”