The ABC-type multidrug transport system

A extensive array of Multidrug resistance transporters that extrude drug compounds out of the cell have been identified as a major cause of bacterial drug resistance.  These proteins prevent intracellular accumulation of toxic compounds, which renders them a major defense mechanism against antimicrobial compounds. 

Efflux pumps not only can expel a broad range of antibiotics owing to their poly-substrate specificity, but can also drive the acquisition of additional resistance mechanisms by lowering intracellular antibiotic concentration and promoting mutation accumulation.  Over-expression of multidrug efflux pumps have been increasingly found to be associated with clinically relevant drug resistance.  However, accumulating evidence also suggests that efflux pumps have important physiological functions in bacteria. The expression of these genes is subject tight regulation in response to various of environmental and physiological signals.

Multidrug resistance (MDR) transporters can be divided into two classes based on their source of energy: (1) Secondary transporters, which use proton gradients to facilitate an antiporter mechanism, and (2) adenosine triphosphate (ATP) binding cassette (ABC) transporters that couple the hydrolysis of ATP to substrate transport across the cell membrane.

Secondary MDR transporters are comprised of four superfamilies: (a) the resistance/nodulation/division family (referred to as the RND family), (b) the multidrug / oligosaccharidyl- lipid / polysaccharide flippase family, (c) the drug/metabolite transporter superfamily, and (d) the highly diverse major facilitator superfamily. 

ABC transporters belong to one of the largest superfamilies of proteins and that either import or export a broad range of substrates that include amino acids, ions, sugars, lipids, and drugs.  The nucleotide binding domain (NBD) of these proteins, also called an ABC (ATP binding cassette), is the hallmark feature of this transporter family. The differences in their substrate specificity are reflected in their overall divergence in their transmembrane domains (TMDs).

Both importing and exporting ABC transporters are found in bacteria.

 

ABC-TYPE MULTIDRUG TRANSPORT SYSTEM GENES IN SCRUB TYPHUS

Within Orientia, numerous genes can be classified as members of the ABC-type transport system. At least five of these genes fall into the ABC-type multidrug resistance sub-group of the transport system. Of these five, two genes have homology to genes in Rickettsia that code for components of the system with ATPase and permease functions. These occur in the Boryong genome at locations 521744-523414 and 977497-979233. A further two genes code for homologous components of the system with ATP-binding protein functions. These occur in the Boryong genome at 667543..669324 and 757701..759368. The final homologous gene can be classified as an ABC transporter substrate binding protein (position 1544972-1545457 in Boryong). There are at least ten other genes that form part of the ABC-type transport system, but which may not be involved in functions that could confer multi-drug resistance.

Genome comparisons indicate that the five genes currently identified as putative members of the  ABC-type multidrug resistance transport system are present in all genomes of O. tsutsugamushi currently examined (14) and in the O. chuto genome.  The genes show substantial levels of both nucleotide and amino acid variation, leaving the question of whether particular mutations could contribute to possible antibiotic resistance to future analyses.