Ketelboeter Laura M, Bardy Sonia L
Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
PLoS One. 2017 Jun 1;12(6):e0178084. doi: 10.1371/journal.pone.0178084. eCollection 2017.
Pyomelanin is a reddish-brown pigment that provides bacteria and fungi protection from oxidative stress, and is reported to contribute to infection persistence. Production of this pigment can be inhibited by the anti-virulence agent 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). The Pseudomonas aeruginosa clinical isolate DKN343 exhibited high levels of resistance to NTBC, and the mechanism of pyomelanin production in this strain was uncharacterized. We determined that pyomelanin production in the clinical Pseudomonas aeruginosa isolate DKN343 was due to a loss of function in homogentisate 1,2-dioxygenase (HmgA). Several potential resistance mechanisms were investigated, and the MexAB-OprM efflux pump is required for resistance to NTBC. DKN343 has a frameshift mutation in NalC, which is a known indirect repressor of the mexAB-oprM operon. This frameshift mutation may contribute to the increased resistance of DKN343 to NTBC. Additional studies investigating the prevalence of resistance in pyomelanogenic microbes are necessary to determine the future applications of NTBC as an anti-virulence therapy.
脓黑素是一种红棕色色素，可为细菌和真菌提供抗氧化应激保护，据报道它有助于感染的持续存在。抗毒力剂2-(2-硝基-4-三氟甲基苯甲酰基)-1,3-环己二酮（NTBC）可抑制这种色素的产生。铜绿假单胞菌临床分离株DKN343对NTBC表现出高度抗性，该菌株中脓黑素产生的机制尚未明确。我们确定临床铜绿假单胞菌分离株DKN343中脓黑素的产生是由于尿黑酸1,2-双加氧酶（HmgA）功能丧失所致。我们研究了几种潜在的抗性机制，发现MexAB-OprM外排泵是对NTBC产生抗性所必需的。DKN343的NalC存在移码突变，NalC是已知的mexAB-oprM操纵子间接阻遏物。这种移码突变可能导致DKN343对NTBC的抗性增加。有必要开展更多研究以调查产脓黑素微生物中的抗性流行情况，从而确定NTBC作为一种抗毒力疗法的未来应用前景。
