Carbapenems have been regarded as potent antibiotics for Gram-negative pathogens [1]. However, they show diminished effectiveness against carbapenem-resistant Enterobacteriaceae. For treating infections caused by carbapenem-resistant Klebsiella pneumoniae, colistin has been recognized as one of the last-resort antibiotics. It has been the most used antibiotic for the last few decades [2]. However, the efficacy of colistin has been compromised by the emergence of colistin resistance including heteroresistance and persister cell formation of K. pneumoniae [3], [4], [5]. Infections caused by colistin-resistant K. pneumoniae can result in higher mortality rates than those caused by colistin-susceptible strains [6].

Although the use of colistin has been withdrawn over time due to its nephrotoxicity and other potential side effects [7], it has been showing a resurgence as a result of the global emergence of MDR bacteria since mid-1990s [8]. However, colistin resistance makes it more difficult to make a choice of antibiotics. Only a few treatment options are currently available for colistin-resistant K. pneumoniae infections [2]. Of these, tigecycline is a broad-spectrum semisynthetic glycylcycline that can inhibit bacterial protein synthesis by binding 30S subunit ribosome [9]. Although high tigecycline resistance rates have been reported [10], tigecycline is known to be generally active against K. pneumoniae infections [11].

While treatment efficacy of tigecycline for K. pneumoniae has been investigated so far, the effect of tigecycline on the susceptibility of K. pneumoniae to other antibiotics has not been explored. Recently, we have found that the development of tigecycline resistance can decrease the virulence of K. pneumoniae associated with reduced production of capsular polysaccharide (CPS) [12]. Decreased CPS is associated with ompK35/36 and ompR expression known to be regulated by exposure to tigecycline [13].

The objective of this study was to investigate if tigecycline exposure could decrease the resistance of colistin-resistant K. pneumoniae strains to colistin and mechanisms that enabled such changes. Whether colistin-resistant strains could be treated by combining antibiotics at low concentrations was also explored.