Umland, Timothy C.;
Schultz, L. Wayne;
MacDonald, Ulrike;
Beanan, Janet M.;
Olson, Ruth;
Russo, Thomas A.
In Vivo -Validated Essential Genes Identified in Acinetobacter baumannii by Using Human Ascites Overlap Poorly with Essential Genes Detected on Laboratory Media
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Media type:
E-Article
Title:
In Vivo -Validated Essential Genes Identified in Acinetobacter baumannii by Using Human Ascites Overlap Poorly with Essential Genes Detected on Laboratory Media
Contributor:
Umland, Timothy C.;
Schultz, L. Wayne;
MacDonald, Ulrike;
Beanan, Janet M.;
Olson, Ruth;
Russo, Thomas A.
Description:
<jats:title>ABSTRACT</jats:title>
<jats:p>
A critical feature of a potential antimicrobial target is the characteristic of being essential for growth and survival during host infection. For bacteria, genome-wide essentiality screens are usually performed on rich laboratory media. This study addressed whether genes detected in that manner were optimal for the identification of antimicrobial targets since the
<jats:italic>in vivo</jats:italic>
milieu is fundamentally different. Mutant derivatives of a clinical isolate of
<jats:named-content content-type="genus-species">Acinetobacter baumannii</jats:named-content>
were screened for growth on human ascites, an
<jats:italic>ex vivo</jats:italic>
medium that reflects the infection environment. A subset of 34 mutants with unique gene disruptions that demonstrated little to no growth on ascites underwent evaluation in a rat subcutaneous abscess model, establishing 18 (53%) of these genes as
<jats:italic>in vivo</jats:italic>
essential. The putative gene products all had annotated biological functions, represented unrecognized or underexploited antimicrobial targets, and could be grouped into five functional categories: metabolic, two-component signaling systems, DNA/RNA synthesis and regulation, protein transport, and structural. These
<jats:italic>A. baumannii in vivo</jats:italic>
essential genes overlapped poorly with the sets of essential genes from other Gram-negative bacteria catalogued in the Database of Essential Genes (DEG), including those of
<jats:named-content content-type="genus-species">Acinetobacter baylyi</jats:named-content>
, a closely related species. However, this finding was not due to the absence of orthologs. None of the 18
<jats:italic>in vivo</jats:italic>
essential genes identified in this study, or their putative gene products, were targets of FDA-approved drugs or drugs in the developmental pipeline, indicating that a significant portion of the available target space within pathogenic Gram-negative bacteria is currently neglected.
</jats:p>
<jats:p>
<jats:bold>IMPORTANCE</jats:bold>
The human pathogen
<jats:named-content content-type="genus-species">Acinetobacter baumannii</jats:named-content>
is of increasing clinical importance, and a growing proportion of isolates are multiantimicrobial-resistant, pan-antimicrobial-resistant, or extremely resistant strains. This scenario is reflective of the general problem of a critical lack of antimicrobials effective against antimicrobial-resistant Gram-negative bacteria, such as
<jats:named-content content-type="genus-species">Pseudomonas aeruginosa</jats:named-content>
,
<jats:named-content content-type="genus-species">Klebsiella pneumoniae</jats:named-content>
,
<jats:italic>Enterobacter</jats:italic>
sp., and
<jats:named-content content-type="genus-species">Escherichia coli</jats:named-content>
. This study identified a set of
<jats:named-content content-type="genus-species">A. baumannii</jats:named-content>
genes that are essential for growth and survival during infection and demonstrated the importance of using clinically relevant media and
<jats:italic>in vivo</jats:italic>
validation while screening for essential genes for the purpose of developing new antimicrobials. Furthermore, it established that if a gene is absent from the Database of Essential Genes, it should not be excluded as a potential antimicrobial target. Lastly, a new set of high-value potential antimicrobial targets for pathogenic Gram-negative bacteria has been identified.
</jats:p>