UNASSIGNED: The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has garnered international concern due to its significant antibiotic resistance. Notably, children exhibit distinct resistance mechanisms compared to adults, necessitating a differential approach to antibiotic selection. A thorough analysis of CRKP\'s epidemiology and drug resistance mechanisms is essential for establishing a robust foundation for clinical anti-infection strategies and precise prevention and control measures.
UNASSIGNED: This study involved the collection of 31 non-repetitive strains from pediatric and adult patients at a tertiary hospital in China, spanning from July 2016 to July 2022, testing for resistance genes, antimicrobial susceptibility, and homology analysis.
UNASSIGNED: Infants (0-1 year) were the largest pediatric CRKP group, with 61.3% of cases. The neonatal intensive care unit (NICU) and pediatrics were the main departments affected. Adults with CRKP had a mean age of 67 years, with the highest prevalence in neurology and emergency ICU. Antimicrobial susceptibility testing revealed that adult CRKP strains exhibited higher resistance to amikacin, ciprofloxacin, cotrimoxazole, and aztreonam compared to pediatric strains. Conversely, pediatric strains showed a higher rate of resistance to ceftazidime/avibactam. The predominant resistance genes identified were bla NDM-5 in children (58.1%) and bla KPC-2 in adults (87.1%), with over 93% of both groups testing positive for extended-spectrum beta-lactamase (ESBL) genes. Multilocus Sequence Typing (MLST) indicated ST2735 and ST11 as the predominant types in children and adults, respectively. Pulsed-field gel electrophoresis (PFGE) identified clonal transmission patterns of ST11 bla KPC-2 and ST15 bla OXA-232 across both age groups. Notably, this study reports the first instance of ST1114-type CRKP co-producing bla NDM-5 and bla OXA-181 in the NICU.
UNASSIGNED: This study reveals distinct resistance mechanisms and epidemiology in CRKP from children and adults. The identified clonal transmission patterns emphasize the need for improved infection control to prevent the spread of resistant strains.

In recent decades, the field of systemic cancer treatment has seen remarkable changes due to advancements in the understanding of cancer\'s biology, immunology, and genetic makeup. As a result, individuals with late-stage cancers are now achieving survival rates that were previously unattainable. The goal of personalized cancer therapy is to enhance clinical outcomes by customizing drug treatments to suit the unique genetic and/or epigenetic profiles of each patient\'s tumor. This approach aims to reduce the side effects commonly associated with ineffective treatments. Advances in genetic sequencing and molecular cytogenetics have been instrumental in identifying cancer-driving mutations and epigenetic irregularities, leading to the development of specific molecular therapies. This review article highlights the progress and success of targeted molecular therapies in treating malignant melanoma, illustrating the concept of personalized cancer treatment.

Mycobacterium abscessus is a non-tuberculous mycobacterial pathogen known to cause pulmonary and skin infections worldwide. Renowned for its multidrug resistance, M. abscessus infections often result in unfavorable clinical outcomes. Clarithromycin plays a pivotal role in treating M. abscessus infections, with resistance commonly leads to treatment failure. While canonical mutations in 23S rRNA residue 2270/2271 are recognized as a major mechanism for acquired clarithromycin resistance, resistant isolates devoid of such mutations have been widely reported. In this study, we conducted a comprehensive investigation into acquired clarithromycin resistance using spontaneous mutants derived from two parental strains characterized by erm(41) T28 and C28 sequevars respectively. A total of 135 resistant mutants were selected from the parental strains. Sequencing of the 78 mutants lacking canonical 2270/2271 mutations identified mutations within the peptidyl-transferase center and in hairpin loops 35, 49, and 74 of the 23S rRNA. Moreover, these noncanonical mutations were identified in 57 out of 1875 genomes of clinical isolates. Thirteen representative mutations were introduced into the bacterial genome via site-directed mutagenesis, and their contribution to macrolide resistance was verified. Mapping these mutations onto the three-dimensional structure of 23S rRNA revealed their localization at the entrance of the nascent peptide exit tunnel, potentially contributing to resistance by disrupting the macrolide binding pocket. The identification of these noncanonical 23S rRNA mutations advances our understanding of macrolide resistance in M. abscessus and underscores their importance as potential markers for detecting clarithromycin resistance.

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Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets.

We used whole-genome sequencing to analyze a collection of 35 fluconazole-resistant and 7 susceptible Candida parapsilosis isolates together with coverage analysis and GWAS techniques to identify new mechanisms of fluconazole resistance. Phylogenetic analysis shows that although the collection is diverse, two persistent clinical lineages were identified. We identified copy number variation (CNV) of two genes, ERG11 and CDR1B, in resistant isolates. Two strains have a CNV at the ERG11 locus; the entire ORF is amplified in one, and only the promoter region is amplified in the other. We show that the annotated telomeric gene CDR1B is actually an artifactual in silico fusion of two highly similar neighboring CDR genes due to an assembly error in the C. parapsilosis CDC317 reference genome. We report highly variable copy numbers of the CDR1B region across the collection. Several strains have increased the expansion of the two genes into a tandem array of new chimeric genes. Other strains have experienced a deletion between the two genes creating a single gene with a reciprocal chimerism. We find translocations, duplications, and gene conversion across the CDR gene family in the C. parapsilosis species complex, showing that it is a highly dynamic family.

Escherichia coli O157:H7 is a globally important foodborne pathogen with implications for food safety. Antibiotic treatment for O157 may potentially contribute to the exacerbation of hemolytic uremic syndrome, and the increasing prevalence of antibiotic-resistant strains necessitates the development of new treatment strategies. In this study, the bactericidal effects and resistance development of antibiotic and bacteriophage monotherapy were compared with those of combination therapy against O157. Experiments involving continuous exposure of O157 to phages and antibiotics, along with genetic deletion studies, revealed that the deletion of glpT and uhpT significantly increased resistance to fosfomycin. Furthermore, we found that OmpC functions as a receptor for the PP01 phage, which infects O157, and FhuA functions as a receptor for the newly isolated SP15 phage, targeting O157. In the glpT and uhpT deletion mutants, additional deletion in ompC, the receptor for the PP01 phage, increased resistance to fosfomycin. These findings suggest that specific phages may contribute to antibiotic resistance by selecting the emergence of gene mutations responsible for both phage and antibiotic resistance. While combination therapy with phages and antibiotics holds promise for the treatment of bacterial infections, careful consideration of phage selection is necessary.IMPORTANCEThe combination treatment of fosfomycin and bacteriophages against Escherichia coli O157 demonstrated superior bactericidal efficacy compared to monotherapy, effectively suppressing the emergence of resistance. However, mutations selected by phage PP01 led to enhanced resistance not only to the phage but also to fosfomycin. These findings underscore the importance of exercising caution in selecting phages for combination therapy, as resistance selected by specific phages may increase the risk of developing antibiotic resistance.

Ovarian cancer is among the most lethal gynecological cancers, primarily due to the lack of specific symptoms leading to an advanced-stage diagnosis and resistance to chemotherapy. Drug resistance (DR) poses the most significant challenge in treating patients with existing drugs. The Food and Drug Administration (FDA) has recently approved three new therapeutic drugs, including two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and niraparib) and one vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) for maintenance therapy. However, resistance to these new drugs has emerged. Therefore, understanding the mechanisms of DR and exploring new approaches to overcome them is crucial for effective management. In this review, we summarize the major molecular mechanisms of DR and discuss novel strategies to combat DR.

Intraspecific genomic diversity brings the potential for an unreported and diverse reservoir of cryptic antibiotic resistance genes in pathogens, as cryptic resistance can occur without major mutations and horizontal transmission. Here, we predicted the differences in the types of antibiotics and genes that induce cryptic and latent resistance between micro-diverse Escherichia coli strains. For example, we hypothesize that known resistance genes will be the culprit of latent resistance within clinical strains. We used a modified functional metagenomics method to induce expression in eight E. coli strains. We found a total of 66 individual genes conferring phenotypic resistance to 11 out of 16 antibiotics. A total of 14 known antibiotic resistance genes comprised 21% of total identified genes, whereas the majority (52 genes) were unclassified cryptic resistance genes. Between the eight strains, 1.2% of core orthologous genes were positive (conferred resistance in at least one strain). Sixty-four percent of positive orthologous genes conferred resistance to only one strain, demonstrating high intraspecific variability of latent resistance genes. Cryptic resistance genes comprised most resistance genes among laboratory and clinical strains as well as natural, semisynthetic, and synthetic antibiotics. Known antibiotic resistance genes primarily conferred resistance to multiple antibiotics from varying origins and within multiple strains. Hence, it is uncommon for E. coli to develop cross-cryptic resistance to antibiotics from multiple origins or within multiple strains. We have uncovered prospective and previously unknown resistance genes as well as antibiotics that have the potential to trigger latent antibiotic resistance in E. coli strains from varying origins.IMPORTANCEIntraspecific genomic diversity may be a driving force in the emergence of adaptive antibiotic resistance. Adaptive antibiotic resistance enables sensitive bacterial cells to acquire temporary antibiotic resistance, creating an optimal window for the development of permanent mutational resistance. In this study, we investigate cryptic resistance, an adaptive resistance mechanism, and unveil novel (cryptic) antibiotic resistance genes that confer resistance when amplified within eight E. coli strains derived from clinical and laboratory origins. We identify the potential of cryptic resistance genes to confer cross-resistance to antibiotics from varying origins and within multiple strains. We discern antibiotic characteristics that promote latent resistance in multiple strains, considering intraspecific diversity. This study may help detect novel resistance genes and functional genes that could become responsible for cryptic resistance among diverse strains and antibiotics, thus also identifying potential novel antibiotic targets and mechanisms.

Candida auris, an emerging and multidrug-resistant fungal pathogen, has led to numerous outbreaks in China. While the resistance mechanisms against azole and amphotericin B have been studied, the development of drug resistance in this pathogen remains poorly understood, particularly in in vivo-generated drug-resistant strains. This study employed pathogen whole-genome sequencing to investigate the epidemiology and drug-resistance mutations of C. auris using 16 strains isolated from two patients. Identification was conducted through Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antimicrobial susceptibilities were assessed using broth microdilution and Sensititre YeastOne YO10. Whole-genome sequencing revealed that all isolates belonged to the South Asian lineage, displaying genetic heterogeneity. Despite low genetic variability among patient isolates, notable mutations were identified, including Y132F in ERG11 and A585S in TAC1b, likely linked to increased fluconazole resistance. Strains from patient B also carried F214L in TAC1b, resulting in a consistent voriconazole minimum inhibitory concentration of 4 µg/mL across all isolates. Furthermore, a novel frameshift mutation in the SNG1 gene was observed in amphotericin B-resistant isolates compared to susceptible ones. Our findings suggest the potential transmission of C. auris and emphasize the need to explore variations related to antifungal resistance. This involves analyzing genomic mutations and karyotypes, especially in vivo, to compare sensitive and resistant strains. Further monitoring and validation efforts are crucial for a comprehensive understanding of the mechanisms of drug resistance in C. auris.