Workplace Reintegration Programs, Policies, and Procedures for Nurses Experiencing Operational Stress Injury: A Scoping Literature Review.

BACKGROUND: Nurses experience elevated rates of operational stress injuries (OSIs). This can necessitate taking leave from work and subsequently engaging in a workplace reintegration process. An unsuccessful process can have long term impacts on a nurse's career, affecting the individual, their family, and broader community, while contributing to nursing shortages. A knowledge gap regarding the workplace reintegration of nurses experiencing mental health challenges, impedes the development and implementation of initiatives that might increase the success of nurses reintegrating into the workplace. This scoping review explored the existing literature concerning workplace reintegration for nurses experiencing OSIs. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) reporting guidelines were utilized. Three key search terms across six databases were employed followed by a qualitative content analysis of the resulting literature. RESULTS: Eight documents were included. The literature exhibited high heterogeneity in objectives, content, and article types. The content analysis revealed five themes: (1) recognizing stigma, (2) elements of successful workplace reintegration, (3) considerations for military nurses, (4) considerations for nurses with substance use disorders, and (5) gaps in the existing literature. CONCLUSION: A paucity of programs, policies, procedures, and research exists regarding workplace reintegration for nurses facing mental health challenges. It is imperative to recognize that nurses may experience OSIs, necessitating mental health support, time off work, and operationally/culturally-specific assistance in returning to work. Innovative and evidence-based approaches to workplace reintegration are needed to enhance the retention of a skilled, experienced, compassionate, and healthy nursing workforce.

Chronic villitis as a distinctive feature of placental injury in maternal SARS-CoV-2 infection.

BACKGROUND: SARS-CoV-2 infection during pregnancy is associated with an increased risk for stillbirth, preeclampsia, and preterm birth. However, this does not seem to be caused by intrauterine fetal infection because vertical transmission is rarely reported. There is a paucity of data regarding the associated placental SARS-CoV-2 histopathology and their relationship with the timing and severity of infection. OBJECTIVE: This study aimed to determine if maternal SARS-CoV-2 infection was associated with specific patterns of placental injury and if these findings differed by gestational age at time of infection or disease severity. STUDY DESIGN: A retrospective cohort study was performed at the University of California San Diego between March 2020 and February 2021. Placentas from pregnancies with a positive SARS-CoV-2 test were matched with 2 sets of controls; 1 set was time-matched by delivery date and sent to pathology for routine clinical indications, and the other was chosen from a cohort of placentas previously collected for research purposes without clinical indications for pathologic examination before the SARS-CoV-2 outbreak. Placental pathologic lesions were defined based on standard criteria and included maternal and fetal vascular malperfusion and acute and chronic inflammatory lesions. A bivariate analysis was performed using the independent Student t test and Pearson chi-square test. A logistic regression was used to control for relevant covariates. Regions of SARS-CoV-2-associated villitis were further investigated using protein-based digital spatial profiling assays on the GeoMx platform, validated by immunohistochemistry, and compared with cases of infectious villitis and villitis of unknown etiology. Differential expression analysis was performed to identify protein expression differences between these groups of villitis. RESULTS: We included 272 SARS-CoV-2 positive cases, 272 time-matched controls, and 272 historic controls. The mean age of SARS-CoV-2 affected subjects was 30.1±5.5 years and the majority were Hispanic (53.7%) and parous (65.7%). SARS-CoV-2 placentas demonstrated a higher frequency of the 4 major patterns of placental injury (all P<.001) than the historic controls. SARS-CoV-2 placentas also showed a higher frequency of chronic villitis and severe chronic villitis (P=.03 for both) than the time-matched controls, which remained significant after controlling for gestational age at delivery (adjusted odds ratio, 1.52; 95% confidence interval, 1.01-2.28; adjusted odds ratio, 2.12; 95% confidence interval, 1.16-3.88, respectively). Digital spatial profiling revealed that programmed death-ligand 1 was increased in villitis-positive regions of the SARS-CoV-2 (logFC, 0.47; adjusted P value =.002) and villitis of unknown etiology (logFC, 0.58; adjusted P value =.003) cases, but it was conversely decreased in villitis-positive regions of the infectious villitis group (log FC, -1.40; adjusted P value <.001). CONCLUSION: Chronic villitis seems to be the most specific histopathologic finding associated with SARS-CoV-2 maternal infection. Chronic villitis involves damage to the vasculosyncytial membrane of the chorionic villi, which are involved in gas and nutrient exchange, suggesting potential mechanisms of placental (and perhaps neonatal) injury, even in the absence of vertical transmission. Surprisingly, changes in protein expression in SARS-CoV-2-associated villitis seem to be more similar to villitis of unknown etiology than to infectious villitis.

Multidimensional digital biomarker phenotypes for mild cognitive impairment: considerations for early identification, diagnosis and monitoring.

Mild Cognitive Impairment (MCI) poses a challenge for a growing population worldwide. Early identification of risk for and diagnosis of MCI is critical to providing the right interventions at the right time. The paucity of reliable, valid, and scalable methods for predicting, diagnosing, and monitoring MCI with traditional biomarkers is noteworthy. Digital biomarkers hold new promise in understanding MCI. Identifying digital biomarkers specifically for MCI, however, is complex. The biomarker profile for MCI is expected to be multidimensional with multiple phenotypes based on different etiologies. Advanced methodological approaches, such as high-dimensional statistics and deep machine learning, will be needed to build these multidimensional digital biomarker profiles for MCI. Comparing patients to these MCI phenotypes in clinical practice can assist clinicians in better determining etiologies, some of which may be reversible, and developing more precise care plans. Key considerations in developing reliable multidimensional digital biomarker profiles specific to an MCI population are also explored.

Differential in vitro susceptibility to ampicillin/ceftriaxone combination therapy among Enterococcus faecalis infective endocarditis clinical isolates.

OBJECTIVES: To investigate the genomic diversity and ß-lactam susceptibilities of Enterococcus faecalis collected from patients with infective endocarditis (IE). METHODS: We collected 60 contemporary E. faecalis isolates from definite or probable IE cases identified between 2018 and 2021 at the University of Pittsburgh Medical Center. We used whole-genome sequencing to study bacterial genomic diversity and employed antibiotic checkerboard assays and a one-compartment pharmacokinetic-pharmacodynamic (PK/PD) model to investigate bacterial susceptibility to ampicillin and ceftriaxone both alone and in combination. RESULTS: Genetically diverse E. faecalis were collected, however, isolates belonging to two STs, ST6 and ST179, were collected from 21/60 (35%) IE patients. All ST6 isolates encoded a previously described mutation upstream of penicillin-binding protein 4 (pbp4) that is associated with pbp4 overexpression. ST6 isolates had higher ceftriaxone MICs and higher fractional inhibitory concentration index values for ampicillin and ceftriaxone (AC) compared to other isolates, suggesting diminished in vitro AC synergy against this lineage. Introduction of the pbp4 upstream mutation found among ST6 isolates caused increased ceftriaxone resistance in a laboratory E. faecalis isolate. PK/PD testing showed that a representative ST6 isolate exhibited attenuated efficacy of AC combination therapy at humanized antibiotic exposures. CONCLUSIONS: We find evidence for diminished in vitro AC activity among a subset of E. faecalis IE isolates with increased pbp4 expression. These findings suggest that alternate antibiotic combinations against diverse contemporary E. faecalis IE isolates should be evaluated.

Composite haemangioendothelioma with neuroendocrine marker differentiation presenting as a pink-brown nodule.

We report a case of a 55-year-old female with an asymptomatic pink-brown nodule. Histological examination demonstrated a composite haemangioendothelioma with positive synaptophysin staining.

In vitro activity of clindamycin, doxycycline, and trimethoprim/sulfamethoxazole against clinical isolates of ß-hemolytic Streptococcus spp. via BD Phoenix and broth microdilution.

We tested 85 isolates of ß-hemolytic Streptococcus spp. against trimethoprim/sulfamethoxazole (TMP/SMX), clindamycin, and doxycycline by broth microdilution (BMD) and BD Phoenix. Susceptibility rates via BMD for TMP/SMX, clindamycin, and doxycycline were 100%, 85.5%, and 56.6%, respectively. TMP/SMX is a potential monotherapy agent for ß-hemolytic Streptococcus skin and soft tissue infections.

A ß-barrel-like tetramer formed by a ß-hairpin derived from Aß.

ß-Hairpins formed by the ß-amyloid peptide Aß are building blocks of Aß oligomers. Three different alignments of ß-hairpins have been observed in the structures of Aß oligomers or fibrils. Differences in ß-hairpin alignment likely contribute to the heterogeneity of Aß oligomers and thus impede their study at high-resolution. Here, we designed, synthesized, and studied a series of ß-hairpin peptides derived from Aß12-40 in one of these three alignments and investigated their solution-phase assembly and folding. These assays reveal the formation of tetramers and octamers that are stabilized by intermolecular hydrogen bonding interactions between Aß residues 12-14 and 38-40 as part of an extended ß-hairpin conformation. X-ray crystallographic studies of one peptide from this series reveal the formation of ß-barrel-like tetramers and octamers that are stabilized by edge-to-edge hydrogen bonding and hydrophobic packing. Dye-leakage and caspase 3/7 activation assays using tetramer and octamer forming peptides from this series reveal membrane-damaging and apoptotic properties. A molecular dynamics simulation of the ß-barrel-like tetramer embedded in a lipid bilayer shows membrane disruption and water permeation. The tetramers and octamers described herein provide additional models of how Aß may assemble into oligomers and supports the hypothesis that ß-hairpin alignment and topology may contribute directly to oligomer heterogeneity.

Mutations in ompK36 differentially impact in vitro synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing Klebsiella pneumoniae.

Objectives: Ceftazidime/avibactam and meropenem/vaborbactam are preferred agents for Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) infections and are often used in combination with other agents. We aimed to characterize the synergy of combinations against KPC-Kp with varying ompK36 genotypes. Methods: KPC-Kp that harboured ompK36 WT, IS5 or glycine-aspartic acid duplication (GD) genotypes were selected. MICs were determined in triplicate. Synergy was assessed by time-kill assays for ceftazidime/avibactam and meropenem/vaborbactam in combination with colistin, gentamicin, tigecycline, meropenem or fosfomycin against 1 × 108 cfu/mL KPC-Kp. Results: KPC-Kp harboured ompK36 WT (n = 5), IS5 (n = 5) or GD (n = 5); 11 were KPC-2 and 4 were KPC-3. All were susceptible to ceftazidime/avibactam and meropenem/vaborbactam. In time-kill analysis, ceftazidime/avibactam and meropenem/vaborbactam 1 × MIC exhibited mean 24 h log-kills of -2.01 and -0.84, respectively. Ceftazidime/avibactam was synergistic in combination with colistin independent of ompK36 genotype. Ceftazidime/avibactam combinations impacted by porin mutations (compared to WT) were meropenem (-5.18 versus -6.62 mean log-kill, P < 0.001) and fosfomycin (-3.98 versus -6.58, P = 0.058). Mean log-kills with meropenem/vaborbactam were greatest in combination with gentamicin (-5.36). In the presence of porin mutations, meropenem/vaborbactam killing activity was potentiated by the addition of colistin (-6.65 versus -0.70, P = 0.03) and fosfomycin (-3.12 versus 1.54, P = 0.003). Conclusions: Our results shed new light on the synergy of ceftazidime/avibactam and meropenem/vaborbactam combinations against KPC-Kp with or without porin mutations. Killing activity of ceftazidime/avibactam with other cell wall active agents was decreased against isolates with porin mutations. On the other hand, some meropenem/vaborbactam combinations demonstrated enhanced killing in the presence of porin mutations.

"Collapsing into Darkness": An Exploratory Qualitative Thematic Analysis of the Experience of Workplace Reintegration among Nurses with Operational Stress Injuries.

BACKGROUND: Nurses are engaged in an unpredictable and dynamic work environment where they are exposed to events that may cause or contribute to physical and/or psychological injuries. Operational stress injury (OSI) may lead to an extended time away from work or nurses leaving the profession altogether. A deliberate focus on the workplace reintegration phase of the mental health recovery process may lead to the increased retention of nurses in their profession. Prior to the creation and implementation of potential solutions to address workplace reintegration, it is imperative to explore the experiences and perceptions of nurses affected by OSI. This qualitative study aims to investigate the experiences and perceptions of nurses (N = 7) employed within a Canadian provincial healthcare system who have attempted workplace reintegration after being off of work with an OSI. METHODS: Nurses were recruited via social media, unit emails, and word of mouth. Data were collected through recorded semi-structured interviews conducted over videoconferencing. Once transcribed, the data were thematically analyzed using an inductive approach. RESULTS: The resulting themes included (1) heroes to zeros, (2) changing the status quo, (3) connection is key, and (4) post-traumatic growth: advocacy and altruism. Study participants indicated both that nursing culture and a cumulation of events contributed to a need for a leave of absence from work and that a formalized process was desired by nurses to assist in returning to work. CONCLUSIONS: The development, implementation, and exploration of innovative policies, procedures, and initiatives to bridge the gap from clinical interventions to workplace reintegration are needed for nurses experiencing OSI. Further research is also needed regarding mental health impacts and appropriate resources to support nurses in their workplace reintegration process after experiencing psychological and/or physical injury.

Correction: Efficacy, Effectiveness, and Quality of Resilience-Building Mobile Health Apps for Military, Veteran, and Public Safety Personnel Populations: Scoping Literature Review and App Evaluation.

[This corrects the article DOI: 10.2196/26453.].

How Do We Keep our Heads above Water? An Embedded Mixed-Methods Study Exploring Implementation of a Workplace Reintegration Program for Nurses Affected by Operational Stress Injury.

BACKGROUND: Nurses are exposed to potentially psychologically traumatic events which can lead to operational stress injuries (OSI). Workplace reintegration after an OSI can be challenging, especially with repeated exposure to potentially traumatic scenarios and workplace demands. A workplace reintegration program (RP) originally developed for police officers may be of benefit for nurses returning to work after an OSI. The purpose of this study is to investigate the perceived need for an RP for nurses, and its potential contextualization and implementation in the nursing context using an implementation science approach. METHODS: This mixed-methods study collected data via questionnaires and focus groups from acute care nurses in Canada (N = 19). Data analysis was conducted using descriptive statistics, thematic analysis, and an organizational readiness assessment. RESULTS: Study participants indicated that formalized processes were rarely used to support nurses returning to work after time off due to mental health challenges. Themes included (1) "The Perfect Storm": the current state of return-to-work, (2) Integral Needs, and (3) A Break in the Clouds: hope for health. CONCLUSIONS: Exploration of innovative programs such as the RP may provide additional support to nurses affected by OSIs. Further research is needed regarding workplace reintegration for nurses, and contextualization and evaluation of the RP.

User Satisfaction With a Daily Supportive Text Message Program (Text4PTSI) for Public Safety Personnel: Longitudinal Cross-Sectional Study.

BACKGROUND: Public safety personnel (PSP) are exposed to traumatic events due to their work environments, which increases the risk of mental health challenges. Providing effective and evidence-based interventions, such as SMS text messaging programs, can improve PSP's overall mental well-being with high user satisfaction rates. OBJECTIVE: This study aims to evaluate users' satisfaction, receptiveness, and perceptions of a cognitive behavioral therapy (CBT)-based supportive SMS text messaging intervention (Text4PTSI). METHODS: Participants self-subscribed to Text4PTSI and received unidirectional cognitive behavioral-based supportive text messages for 6 months. Participants completed a web-based survey delivered via SMS text message at enrollment, and 6 weeks, 3 months, and 6 months post enrollment. Respondents' perception and receptivity of the program were assessed using a questionnaire measured on a 5-point Likert scale. Data were collected as categorical variables, and overall satisfaction with the Text4PTSI program was measured on a scale from 0 to 100. RESULTS: There were 131 subscribers to the Text4PTSI program; however, only 81 subscribers responded to the survey, producing 100 survey responses across the 3 follow-up time points. The overall mean score of satisfaction was 85.12 (SD 13.35). More than half of the survey responses agreed or strongly agreed that Text4PTSI helped participants cope with anxiety (79/100 responses, 79%), depressive symptoms (72/100 responses, 72%), and loneliness (54/100 responses, 54%). Similarly, most of the survey responses agreed or strongly agreed that the Text4PTSI program made respondents feel connected to a support system, improved their overall mental well-being (84/100 responses, 84%), felt more hopeful about managing concerns about their mental health or substance use (82 out of responses, 82%), and helped enhance their overall quality of life (77/100 responses, 77%). The available survey responses suggest that the majority always read the supportive text messages (84/100 responses, 84%), took time to reflect on each message (75/100 responses, 75%), and returned to read the text messages more than once (76/100 responses, 76%). CONCLUSIONS: PSP who responded to the follow-up surveys reported high user satisfaction and appreciation for receiving the Text4PTSI intervention during the 6-month program. The reported satisfaction with the service provided could pave the way to ensuring a better uptake of the service with potential effectiveness to end users.

Moving Forward from Moral Injury: A Mixed Methods Study Investigating the Use of 3MDR for Treatment-Resistant PTSD.

BACKGROUND: Exposure to trauma and potentially morally injurious events may lead to moral injury (MI). The link between MI and posttraumatic stress disorder (PTSD) may have particularly relevant implications for treatment-resistant PTSD (TR-PTSD). Multi-modal Motion-Assisted Memory Desensitization and Reconsolidation (3MDR), a technology-assisted exposure-based trauma therapy that has been used in the treatment of PTSD, may also be an acceptable modality for patients in the treatment of TR-PTSD and MI. This proof-of-concept study aimed to investigate (1) whether MI co-occurs in military members (MMs) and veterans with TR-PTSD, and (2) the perspectives of MMs and veterans with TR-PTSD utilizing 3MDR for MI. METHODS: This study employed a mixed-methods clinical trial. Military Members and veterans participated in this study (N = 11) through self-reported questionnaires, video recordings of treatment sessions, and semi-structured interviews post-session and post-intervention, with longitudinal follow-up to 6 months. RESULTS: MI scores correlated with self-reported measures of mental health symptoms related to PTSD. The thematic analysis revealed three emergent themes: (1) Realities of War, (2) Wrestling Scruples, and (3) Moral Sensemaking. CONCLUSION: MI was highly correlated with TR-PTSD and themes regarding MI. This result, while preliminary, allows for the postulation that MI may be contributing to the continuation of PTSD symptoms in TR-PTSD, and that 3MDR may be an acceptable modality for addressing these symptoms in MMs and veterans.

Impact of ompk36 genotype and KPC subtype on the in vitro activity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producing K. pneumoniae clinical isolates.

Objectives: The availability of new ß-lactam/ß-lactamase inhibitors ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam have redefined contemporary treatment of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections. We aimed to characterize and contrast the in vitro activity of these agents against genetically diverse KPC-Kp clinical isolates. Methods: We analysed genomes of 104 non-consecutive KPC-Kp isolates and compared the in vitro antibiotic activity by KPC subtype and ompK36 genotype. MICs were determined in triplicate by CLSI methods. Twenty representative isolates were selected for time-kill analyses against physiological steady-state and trough concentrations, as well as 4× MIC for each agent. Results: Fifty-eight percent and 42% of isolates harboured KPC-2 and KPC-3, respectively. OmpK36 mutations were more common among KPC-2- compared with KPC-3-producing Kp (P < 0.0001); mutations were classified as IS5 insertion, glycine-aspartic acid insertion at position 134 (GD duplication) and other mutations. Compared to isolates with WT ompK36, ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam MICs were elevated for isolates with IS5 by 2-, 4- and 16-fold, respectively (P < 0.05 for each). Against isolates with GD duplication, imipenem/relebactam and meropenem/vaborbactam MICs were increased, but ceftazidime/avibactam MICs were not. In time-kill studies, ceftazidime/avibactam-mediated killing correlated with ceftazidime/avibactam MICs, and did not vary across ompK36 genotypes. Imipenem/relebactam was not bactericidal against any isolate at trough concentrations. At steady-state imipenem/relebactam concentrations, regrowth occurred more commonly for isolates with IS5 mutations. Log-kills were lower in the presence of meropenem/vaborbactam for isolates with GD duplication compared with IS5 mutations. Conclusions: Our investigation identified key genotypes that attenuate, to varying degrees, the in vitro activity for each of the new ß-lactam/ß-lactamase inhibitors. Additional studies are needed to translate the importance of these observations into clinical practice.

Text4PTSI: A Promising Supportive Text Messaging Program to Mitigate Psychological Symptoms in Public Safety Personnel.

BACKGROUND: Public safety personnel experience various mental health conditions due to their work's complex and demanding nature. There are barriers to seeking support and treatment; hence, providing innovative and cost-effective interventions can help improve mental health symptoms in public safety personnel. OBJECTIVE: The study aimed to evaluate the impact of Text4PTSI on depression, anxiety, trauma, and stress-related symptoms, and the resilience of public safety personnel after six months of providing supportive text message intervention. METHODS: Public safety personnel subscribed to Text4PTSI and received daily supportive and psychoeducational SMS text messages for six months. Participants were invited to complete standardized self-rated web-based questionnaires to assess depression, anxiety, posttraumatic stress disorder (PTSD), and resilience symptoms measured on the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 scale (GAD-7), Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C), and the Brief Resilience Scale (BRS), respectively. The assessment of mental health conditions was conducted at baseline (enrolment) and six weeks, three months, and six months after enrollment. RESULTS: One hundred and thirty-one subscribers participated in the Text4PTSI program, and eighteen completed both the baseline and any follow-up survey. A total of 31 participants completed the baseline survey and 107 total surveys were recorded at all follow-up time points. The baseline prevalence of psychological problems among public safety personnel were as follows: likely major depressive disorder (MDD) was 47.1%, likely generalized anxiety disorder (GAD) was 37.5%, low resilience was 22.2%, and likely PTSD was 13.3%. At six months post-intervention, the prevalence of likely MDD, likely GAD, and likely PTSD among respondents reduced; however, a statistically significant reduction was reported only for likely MDD (-35.3%, X2 (1) = 2.55, p = 0.03). There was no significant change in the prevalence of low resilience between baseline and post-intervention. There was a decrease in the mean scores on the PHQ-9, GAD-7, PCL-C, and the BRS from baseline to post-intervention by 25.8%, 24.7%, 9.5%, and 0.3%, respectively. However, the decrease was only statistically significant for the mean change in GAD-7 scores with a low effect size (t (15) = 2.73, p = 0.02). CONCLUSIONS: The results of this study suggest a significant reduction in the prevalence of likely MDD as well as the severity of anxiety symptoms from baseline to post-intervention for subscribers of the Text4PTSI program. Text4PTSI is a cost-effective, convenient, and easily scalable program that can augment other services for managing the mental health burdens of public safety personnel.

Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29.

This paper describes the synthesis and stereochemical determination of Novo29 (clovibactin), a new peptide antibiotic that is related to teixobactin and is active against Gram-positive bacteria. Novo29 is an eight-residue depsipeptide that contains the noncanonical amino acid hydroxyasparagine of hitherto undetermined stereochemistry in a macrolactone ring. The amino acid building blocks Fmoc-(2R,3R)-hydroxyasparagine-OH and Fmoc-(2R,3S)-hydroxyasparagine-OH were synthesized from (R,R)- and (S,S)-diethyl tartrate. Novo29 and epi-Novo29 were then prepared by solid-phase peptide synthesis using these building blocks. Correlation with an authentic sample of Novo29 through 1H NMR spectroscopy, LC-MS, and in vitro antibiotic activity established that Novo29 contains (2R,3R)-hydroxyasparagine. X-ray crystallography reveals that epi-Novo29 adopts an amphiphilic conformation, with a hydrophobic surface and a hydrophilic surface. Four sets of epi-Novo29 molecules pack in the crystal lattice to form a hydrophobic core. The macrolactone ring adopts a conformation in which the main-chain amide NH groups converge to create a cavity, which binds ordered water and acetate anion. The amphiphilic conformation of epi-Novo29 is reminiscent of the amphiphilic conformation adopted by the related antibiotic teixobactin and its derivatives, which contains a hydrophobic surface that interacts with the lipids of the bacterial cell membrane and a hydrophilic surface that interacts with the aqueous environment. Molecular modeling suggests that Novo29 can adopt an amphiphilic conformation similar to teixobactin, suggesting that Novo29 may interact with bacteria in a similar fashion to teixobactin.

Isobactins: O-acyl isopeptide prodrugs of teixobactin and teixobactin derivatives.

The antibiotic teixobactin is a promising drug candidate against drug-resistant pathogens, such as MRSA and VRE, but forms insoluble gels that may limit intravenous administration. O-Acyl isopeptide prodrug analogues of teixobactin circumvent the problem of gel formation while retaining antibiotic activity. The teixobactin prodrug analogues contain ester linkages between Ile6 and Ser7, Ile2 and Ser3, or between both Ile6 and Ser7 and Ile2 and Ser3. Upon exposure to physiological pH, the prodrug analogues undergo clean conversion to the corresponding amides, with half-lives between 13 and 115 min. Prodrug analogues containing lysine, arginine, or leucine at position 10 exhibit good antibiotic activity against a variety of Gram-positive bacteria while exhibiting little or no cytotoxicity or hemolytic activity. Because O-acyl isopeptide prodrug analogues of teixobactin exhibit clean conversion to the corresponding teixobactin analogues with reduced propensity to form gels, it is anticipated that teixobactin prodrugs will be superior to teixobactin as drug candidates.

Teixobactin kills bacteria by a two-pronged attack on the cell envelope.

Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance1-3. Teixobactin4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan5. Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a ß-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin4. The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates.