First description of a clinical glutamine-dependent Escherichia coli with a missense mutation in the glnA

Small-colony variant (SCV) is a collective term for mutant strains that grow slowly and show atypical colony morphology [1,2]. SCVs are more resistant to some antibiotics than their wild-type strains are, and usually cause persistent and recurrent infections in clinical practice [3,4]. The occurrence of SCVs is usually due to mutations in genes involved in metabolic processes related to the bacterial electron transport chain [5]. SCVs have been isolated from a variety of infection sites, including tissue, bone, and device-associated [6] sites, and can increase resistance to trimethoprim/sulfamethoxazole or aminoglycosides [1,7,8]. Although there are relatively few studies on SCV in Escherichia coli, mutations in genes such as yigP [8], hemA [9], hemB [4], lipA [10], thyA [11], and can [12] have been reported as causes of SCVs. Moreover, E. coli SCVs have been isolated from urinary tract infection [11,13], bacteraemia [12,14], and chronic hip infection [4] samples and are considered clinically important [1]. In clinical microbiology testing, it is known that SCVs such as hemin- or thymidine-dependent SCVs cannot grow in Muller-Hinton medium due to their nutrient requirement, and therefore, results of antimicrobial susceptibility testing cannot be obtained by testing methods conforming to the CLSI and EUCAST [11,15].

Glutamine synthetase is not only responsible for glutamine biosynthesis but also for the assimilation of ammonia into glutamate through a coupled reaction with glutamate synthase [16]. The common form of glutamine synthetase is a dodecameric enzyme with identical subunits of approximately 55 kDa, encoded by glnA. The enzyme consists of 12 identical subunits arranged as two superimposed hexagonal rings that are held together by both hydrophobic interactions and hydrogen bonding between the subunits [17]. Glutamine-dependent Salmonella strains that require glutamine for growth have been isolated in starvation and transposon mutagenesis experiments, and have been reported to exhibit mutations in the glnA gene encoding glutamine synthetase [18,19]. However, there are no reports of glutamine-dependent SCV strains other than Salmonella or of any clinical isolates. In this study, we examined the genetic and growth changes in glutamine-dependent E. coli isolated from the blood culture of a patient.

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