Biology subjects

Subils, T.

Publications and source records attributed to Subils, T..

3 recordsLinked to original sources

bioRxiv2022

The Iron Content of Human Serum Albumin Modulates the Susceptibility of Acinetobacter baumannii to Cefiderocol

Mortality rates of patients infected with Acinetobacter baumannii treated with cefiderocol (CFDC) were not as favorable as the best available treatment for pulmonary and bloodstream infections. Previous studies showed that the presence of human serum albumin (HSA) or HSA-containing fluids like human pleural fluid (HPF) or human serum (HS) in the growth medium is correlated with a decrease in the expression of genes associated with high-efficiency iron uptake systems. These observations may explain the less-than-ideal performance of CFDC in pulmonary and bloodstream infections because ferric siderophore transporters enhance penetration of CFDC into the cells cytosol. Removal of HSA from HPF or HS resulted in a reduction of the minimal inhibitory concentration of CFDC. Concomitant with these results, there was an enhancement of the expression of genes associated with high-efficiency iron uptake systems. In addition to inducing modifications in iron-uptake gene expression, removal of HSA also decreased the expression of {beta}-lactam resistance genes. Taken together, these observations indicate that environmental HSA has a role in the expression levels of selected A. baumannii. Furthermore, removal of iron from HSA had the same effect as removal of HSA on the expression of genes associated with high-efficiency iron uptake systems, suggesting that at least one of the mechanisms by which HSA regulates the expression of selected genes is through acting as an iron supplier. IMPORTANCECefiderocol (CFDC) is a new antibiotic that combines its major bactericidal activity, i.e., inhibition of the Gram-negative bacterial cell wall synthesis, with a first in its class mechanism of cell penetration. The siderophore-like moiety facilitates entry through receptors that recognize ferric-siderophore complexes. Recent trials showed that treating pulmonary and bloodstream Acinetobacter baumannii infections with CFDC did not result in the same outcomes as treating other pathogens. Our studies indicated that exposure to human fluids that contain human serum albumin (HSA) increases the MIC values of CFDC. Results described in this work show that HSA is responsible for a reduction in susceptibility of A. baumannii to CFDC. Furthermore, the presence of HSA in the milieu produces a reduction in levels of expression of proteins associated with high-affinity iron uptake systems and enhanced expression of {beta}-lactam resistance-associated genes. Deferration of HSA was accompanied by a loss of the ability to modify these genes expression levels. These results indicate that the microbiological activity of CFDC towards A. baumannii is attenuated in the presence of HSA-containing fluids. This unique insight opens up new avenues of investigation. Understanding this phenomenons molecular mechanism will help define methodologies to increase treatment efficiency.

microbiology↗

bioRxiv2021

Impact of Human Serum Proteins on Susceptibility of Acinetobacter baumannii to Cefiderocol: role of iron transport

Cefiderocol is a siderophore antibiotic that co-opts iron transporters to facilitate cell entry. We show that genes related to iron uptake systems and resistance to {beta}-lactams in Acinetobacter baumannii have altered expression levels in the presence of human serum, human serum albumin, or human pleural fluid. Cefiderocol MICs are also raised in the presence of the mentioned fluids. Clinical response in A. baumannii infections may be related to the interplay of these human factors.

microbiology↗

bioRxiv2021

Interplay between meropenem and human serum albumin on expression of carbapenem resistance genes and natural competence in Acinetobacter baumannii

Acinetobacter baumannii A118, a mostly susceptible strain, and AB5075, carbapenem-resistant, were cultured in L broth or L broth with different supplements: 3.5% human serum albumin (HSA), human serum (HS), meropenem, or meropenem plus 3.5% HSA. Natural transformation levels were enhanced in A. baumannii A118 and AB5075 cultured in medium supplemented with 3.5 % HSA. Addition of meropenem plus 3.5% HSA caused synergistic enhancement of natural transformation in A. baumannii A118. Medium containing 3.5% HSA or meropenem enhanced the expression levels of the competence and type IV pilus associated genes. The combination meropenem plus 3.5% HSA produced a synergistic augmentation in the expression levels of many of these genes. The addition of HS, which has a high content of HSA, was also an inducer of these genes. Cultures in medium supplemented with HS or 3.5% HSA also affected resistance genes, which were expressed at higher or lower levels depending on the modification required to enhance resistance. The inducing or repressing activity of these modulators also occurred in three more carbapenem-resistant strains tested. An exception was the A. baumannii AMA16 blaNDM-1 gene, which was repressed in the presence of 3.5% HSA. In conclusion, HSA produces an enhancement of natural transformation and a modification in expression levels of competence genes and antibiotic resistance. Furthermore, when HSA is combined with carbapenems, which may produce stronger cellular stress, the A. baumannii responds increasing the levels of expression of genes involved in natural competence. This process may favor the acquisition of foreign DNA and accelerate evolution. ImportanceAcinetobacter baumannii causes a variety of nosocomial- and community-infections that are usually resistant to multiple antimicrobial agents. As new strains acquire more resistance genes, these infections become harder to treat, and mortality can reach up to 39%. The high genomic plasticity exhibited by A. baumannii must be the consequence of numerous mechanisms that include acquiring foreign DNA and recombination. Here, we describe the ability of A. baumannii to induce competence genes when exposed to environments that resemble those found in the human body during untreated infection or after administration of carbapenems. In this latter scenario expression of genes related to resistance also modify their expression levels such that resistance is increased. The contributions of this article are two-pronged. First, when A. baumannii is exposed to substances present during infection, it responds, augmenting the ability to capture DNA and accelerate evolution. Second, in those conditions, the bacterium also modifies the expression of resistance genes to increase its resistance levels. In summary, recognition of substances that are naturally (HSA) or artificially (treatment with carbapenems) induces A. baumannii to defend, enhancing resistance and increasing the chances of acquiring new resistance mechanisms.

microbiology↗