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The emergence and rapid spread of the mobile colistin resistance gene mcr-1 among bacterial species and hosts significantly challenge the efficacy of "last-line" antibiotic colistin. Previously, we reported silver nitrate and auranofin serve as colistin adjuvants for combating mcr-1-positive bacteria. Herein, we uncovered more gold-based drugs and nanoparticles, and found that they exhibited varying degree of synergisms with colistin on killing mcr-1-positive bacteria. However, pre-activation of the drugs by either glutathione or N-acetyl cysteine, thus releasing and accumulating gold ions, is perquisite for their abilities to substitute zinc cofactor from MCR-1 enzyme. X-ray crystallography and biophysical studies further supported the proposed mechanism. This study not only provides basis for combining gold-based drugs and colistin for combating mcr-1-positive bacterial infections, but also undoubtedly opens a new horizon for metabolism details of gold-based drugs in overcoming antimicrobial resistance. [ABSTRACT FROM AUTHOR]

The presence of ionic titanium in the serum of patients with titanium implants is currently unexplained. This is presumed due to corrosion, and yet the serum titanium concentration measured in patients is far greater than that predicted by its solubility. The binding of titanium ion as Ti(IV) to human transferrin (hTF) in serum indicates that Ti(IV) ions interact with human physiology. This is an intriguing finding since there is currently no known role for titanium ions in human physiology. Thus, understanding the factors that determine in vivo titanium ion release is relevant to further understanding this metal’s interactions with human biochemistry. The present study sought to determine the extent of titanium ion release of into human serum in vitro, and the role of citrate, lactate and hTF in this process. It was found that, when surgical devices of commercially pure titanium were placed into human serum, citrate and lactate concentrations were the prime determinants of titanium release. Crystallography revealed Ti(IV) bound to hTF in the presence of citrate alone, signalling that citrate can act as an independent ligand for Ti(IV) binding to hTF. Based on these findings, a two-stage process of titanium ion release into human serum that is dependent upon both citrate and hTF is proposed to explain the ongoing presence of titanium ion in human subjects with implanted titanium devices. [ABSTRACT FROM AUTHOR]

Although the presence of titanium wear particles released into tissues is known to induce local inflammation following the therapeutic implantation of titanium devices into humans, the role that titanium ions play in adverse tissue responses has received little attention. Support that ongoing titanium ion release occurs is evidenced by the presence of ionic titanium bound to transferrin in blood, and ongoing excretion in the urine of patients with titanium devices. However, as reports documenting the presence of titanium within tissues do not distinguish between particulate and ionic forms due to technical challenges, the degree to which ionic titanium is released into tissues is unknown. To determine the potential for titanium ion release into tissues, this study evaluates available in vitro evidence relating to the release of ionic titanium under physiological conditions. This is a systematic literature review of studies reporting titanium ion release into solutions from titanium devices under conditions replicating the interstitial pH and constituents. Inclusion and exclusion criteria were defined. Of 452 articles identified, titanium ions were reported in nine media relevant to human biology in seventeen studies. Only one study, using human serum replicated both physiological pH and the concentration of constituents while reporting the presence of titanium ions. While there is insufficient information to explain the factors that contribute to the presence of titanium ions in serum of humans implanted with titanium devices, currently available information suggests that areas of future inquiry include the role of transferrin and organic acids. [ABSTRACT FROM AUTHOR]