Diaminoquinazoline MMV675968 from Pathogen Box inhibits Acinetobacter baumannii growth through targeting of dihydrofolate reductase

• Published in: Scientific reports Vol. 9; no. 1; pp. 15625 - 8
• Main Authors: Songsungthong, Warangkhana, Yongkiettrakul, Suganya, Bohan, Louise E., Nicholson, Eric S., Prasopporn, Sunisa, Chaiyen, Pimchai, Leartsakulpanich, Ubolsree
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-10-2019; Nature Publishing Group
• Subjects: 631/154; 631/326; 631/337; Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Acinetobacter baumannii - enzymology; Acinetobacter baumannii - growth & development; Acinetobacter Infections - microbiology; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Dihydrofolate reductase; E coli; Folic Acid Antagonists - pharmacology; Global health; Health risks; Humanities and Social Sciences; Humans; Microbial Sensitivity Tests; Minimum inhibitory concentration; multidisciplinary; Pathogens; Quinazolines - chemistry; Quinazolines - pharmacology; Science; Science (multidisciplinary); Tetrahydrofolate Dehydrogenase - genetics; Tetrahydrofolate Dehydrogenase - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-52176-8

Antibiotic resistance in
Acinetobacter baumannii
is a major global health threat. New drugs with novel chemical structures are needed to overcome a myriad of resistance mechanisms in
A. baumannii
. In this study, we screened an open-source Pathogen Box library for anti-
A. baumannii
compounds. Compound MMV675968 (a diaminoquinazoline analog) was the only non-reference compound found to inhibit the growth of all four
A. baumannii
test strains with IC
50
of 0.6–2.7 μM, IC
90
of 0.7–3.9 μM, and MIC of 1.6–10 μM. We showed that MMV675968 targeted
A. baumannii
dihydrofolate reductase (
Ab
DHFR) as determined by an
E. coli
surrogate whose growth was dependent on
Ab
DHFR function and by an
in vitro
DHFR activity assay. Additionally, chemical scaffolds of DHFR inhibitors that are effective as antibiotics against
A. baumannii
were identified using an
in vitro
DHFR activity assay and
A. baumannii
growth inhibition. MMV675968 was the most potent among DHFR inhibitors tested in inhibiting
A. baumannii
growth. This study shows for the first time that MMV675968 inhibits
A. baumannii
growth via selective inhibition of
Ab
DHFR and is therefore a promising scaffold for further antibiotic development against
A. baumannii
.