Sha Cao

Bio: Sha Cao is an academic researcher from Uppsala University. The author has contributed to research in topics: Medicine & Bacillus anthracis. The author has an hindex of 11, co-authored 37 publications receiving 1434 citations. Previous affiliations of Sha Cao include Huazhong Agricultural University.

Selection of resistant bacteria at very low antibiotic concentrations.

Abstract: The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.

In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii.

Abstract: Objectives Widespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants. Methods A thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity. Results MIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin. Conclusions Its superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.

FimH alleles direct preferential binding of Salmonella to distinct mammalian cells or to avian cells.

Abstract: This study aimed to determine whether allelic variants of the FimH adhesin from Salmonella enterica confer differential bacterial binding to different types of mammalian cells [murine bone marrow-derived dendritic cells (DCs) and HEp-2 cells] and chicken leukocytes. Although the type 1 fimbriated S. enterica serovar Typhimurium strains AJB3 (SR-11 derivative) and SL1344 both aggregated yeast cells, only the former bound efficiently to DCs and HEp-2 cells. Type 1 fimbriae-mediated binding to DCs having previously been shown to require the FimH adhesin and to be inhibited by mannose, FimH sequences from strains SL1344 and AJB3 were compared and found to differ by only one residue, asparagine 158 in SL1344 being replaced by a tyrosine in AJB3. The importance of residue 158 for FimH-mediated binding was further confirmed in recombinant Escherichia coli expressing S. enterica type 1 fimbriae with a variety of substitutions engineered at this position. Additional studies with the ‘non-adhesive’ FimH of a type 2 fimbriated S. enterica serovar Gallinarum showed that this FimH did not mediate bacterial binding to murine DCs or HEp-2 cells. However, the type 2 FimH significantly improved bacterial adhesion to chicken leukocytes, in comparison to the type 1 FimH of strain AJB3, attributing for the first time a function to the type 2 fimbriae of S. enterica. Consequently, our data show that allelic variation of the S. enterica FimH adhesin directs not only host-cell-specific recognition, but also distinctive binding to mammalian or avian receptors. It is most relevant that this allele-specific binding profile parallels the host specificity of the respective FimH-expressing pathogen.

Alternative Evolutionary Pathways for Drug-Resistant Small Colony Variant Mutants in Staphylococcus aureus.

Abstract: Staphylococcus aureus is known to generate small colony variants (SCVs) that are resistant to aminoglycoside antibiotics and can cause persistent and recurrent infections. The SCV phenotype is unst ...

A mechanism-based pharmacokinetic/pharmacodynamic model allows prediction of antibiotic killing from MIC values for WT and mutants

Abstract: Objectives: In silico pharmacokinetic/pharmacodynamic (PK/PD) models can be developed based on data from in vitro time-kill experiments and can provide valuable information to guide dosing of antib ...

Tackling antibiotic resistance: the environmental framework

Abstract: Antibiotic resistance is a threat to human and animal health worldwide, and key measures are required to reduce the risks posed by antibiotic resistance genes that occur in the environment. These measures include the identification of critical points of control, the development of reliable surveillance and risk assessment procedures, and the implementation of technological solutions that can prevent environmental contamination with antibiotic resistant bacteria and genes. In this Opinion article, we discuss the main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment.

Microbiological effects of sublethal levels of antibiotics

Abstract: The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

The role of the natural environment in the emergence of antibiotic resistance in Gram-negative bacteria

Abstract: During the past 10 years, multidrug-resistant Gram-negative Enterobacteriaceae have become a substantial challenge to infection control. It has been suggested by clinicians that the effectiveness of antibiotics is in such rapid decline that, depending on the pathogen concerned, their future utility can be measured in decades or even years. Unless the rise in antibiotic resistance can be reversed, we can expect to see a substantial rise in incurable infection and fatality in both developed and developing regions. Antibiotic resistance develops through complex interactions, with resistance arising by de-novo mutation under clinical antibiotic selection or frequently by acquisition of mobile genes that have evolved over time in bacteria in the environment. The reservoir of resistance genes in the environment is due to a mix of naturally occurring resistance and those present in animal and human waste and the selective effects of pollutants, which can co-select for mobile genetic elements carrying multiple resistant genes. Less attention has been given to how anthropogenic activity might be causing evolution of antibiotic resistance in the environment. Although the economics of the pharmaceutical industry continue to restrict investment in novel biomedical responses, action must be taken to avoid the conjunction of factors that promote evolution and spread of antibiotic resistance.

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

Abstract: Surface-associated microbial communities, called biofilms, are present in all environments. Although biofilms play an important positive role in a variety of ecosystems, they also have many negative effects, including biofilm-related infections in medical settings. The ability of pathogenic biofilms to survive in the presence of high concentrations of antibiotics is called "recalcitrance" and is a characteristic property of the biofilm lifestyle, leading to treatment failure and infection recurrence. This review presents our current understanding of the molecular mechanisms of biofilm recalcitrance toward antibiotics and describes how recent progress has improved our capacity to design original and efficient strategies to prevent or eradicate biofilm-related infections.