Effects of Sub-Minimum Inhibitory Concentrations of Imipenem and Colistin on Expression of Biofilm-Specific Antibiotic Resistance and Virulence Genes in Acinetobacter baumannii Sequence Type 1894

Abstract

Antibiotics at suboptimal doses promote biofilm formation and the development of antibiotic resistance. The underlying molecular mechanisms, however, were not investigated. Here, we report the effects of sub-minimum inhibitory concentrations (sub-MICs) of imipenem and colistin on genes associated with biofilm formation and biofilm-specific antibiotic resistance in a multidrug-tolerant clinical strain of Acinetobacter baumannii Sequence Type (ST) 1894. Comparative transcriptome analysis was performed in untreated biofilm and biofilm treated with sub-MIC doses of imipenem and colistin. RNA sequencing data showed that 78 and 285 genes were differentially expressed in imipenem and colistin-treated biofilm cells, respectively. Among the differentially expressed genes (DEGs), 48 and 197 genes were upregulated exclusively in imipenem and colistin-treated biofilm cells, respectively. The upregulated genes included those encoding matrix synthesis (pgaB), multidrug efflux pump (novel00738), fimbrial proteins, and homoserine lactone synthase (AbaI). Upregulation of biofilm-associated genes might enhance biofilm formation when treated with sub-MICs of antibiotics. The downregulated genes include those encoding DNA gyrase (novel00171), 30S ribosomal protein S20 (novel00584), and ribosome releasing factor (RRF) were downregulated when the biofilm cells were treated with imipenem and colistin. Downregulation of these genes affects protein synthesis, which in turn slows down cell metabolism and makes biofilm cells more tolerant to antibiotics. In this investigation, we also found that 5 of 138 small RNAs (sRNAs) were differentially expressed in biofilm regardless of antibiotic treatment or not. Of these, sRNA00203 showed the highest expression levels in biofilm. sRNAs regulate gene expression and are associated with biofilm formation, which may in turn affect the expression of biofilm-specific antibiotic resistance. In summary, when biofilm cells were exposed to sub-MIC doses of colistin and imipenem, coordinated gene responses result in increased biofilm production, multidrug efflux pump expression, and the slowdown of metabolism, which leads to drug tolerance in biofilm. Targeting antibiotic-induced or repressed biofilm-specific genes represents a new strategy for the development of innovative and effective treatments for biofilm-associated infections caused by A. baumannii.

Phenotypic Traits and Probiotic Functions of Lactiplantibacillus plantarum Y42 in Planktonic and Biofilm Forms

“…Our study showed that L. plantarum Y42 in biofilm form, compared with that in planktonic form, was more tolerant to acids, bile salts, temperature, and gastro-intestinal fluids. It was reported that some microorganisms will quickly form biofilms to protect cells when exposed to adverse environments [ 42 ]. Tetragenococcus halophilus was found to survive better in the biofilm form than in the planktonic form when subjected to heat and oxidative stress, according to Yao et al [ 17 ].…”

Genomics: Infectious Disease and Host–Pathogen Interaction

“…Jahan and co-workers reviewed the complex mechanism of biofilm formation and its link to the pathogenicity of the bacterium Salmonella typhi , the causative agent of typhoid fever [ 3 ]. In another study, Shenkutie et al found that biofilm-specific antibiotic resistance and the virulence genes of Acinetobacter baumannii can be induced by sub-minimum inhibitory concentrations of imipenem and colistin, leading to higher antibiotic tolerance in biofilm formation [ 1 ]. On the other hand, unexpectedly, the recombinant SARS-CoV-2 spike protein and mouse coronavirus are able to inhibit biofilm formation of common bacterial pathogens such as Streptococcus pneumoniae and Staphylococcus aureus .…”

“…This Special Issue of the International Journal of Molecular Sciences entitled “Genomics: Infectious Disease and Host –Pathogen Interaction” contains twelve original articles and three reviews that provide new insights into infectious diseases with regard to biofilm formation [ 1 , 2 , 3 ], diagnostics [ 4 ], vaccine development [ 5 ], and host–pathogen interaction [ 6 , 7 ]; these insights are based on genomic [ 8 , 9 , 10 , 11 , 12 ], transcriptomic [ 13 , 14 ], and microbiomic [ 15 ] studies.…”

Correlation between Perturbation of Redox Homeostasis and Antibiofilm Capacity of Phytochemicals at Non-Lethal Concentrations

“…For instance, cannabidiol at the sub-MIC dose of 6.25 μg/mL did not decrease the biofilm mass after 1 day, while inhibition of biofilm mass by 28% and 39% was seen after 2 and 3 days, respectively [ 20 ]. Antibiotics alone at sub-MIC doses are claimed to promote biofilm formation and the development of antibiotic resistance [ 21 ]. The synergic effect of phytochemicals at sub-lethal doses and drugs has been tested and found very promising.…”