Biology subjects

Raza, H.

Publications and source records attributed to Raza, H..

3 recordsLinked to original sources

bioRxiv2026

DISRUPTION OF A DNA REPAIR PROTEIN PROMOTES ANTIBIOTIC RESISTANCE IN ACINETOBACTER BAUMANNII

Acinetobacter baumannii is a high priority Gram negative opportunistic pathogen known for its high rates of multidrug resistance (MDR). Minocycline (MIN), a tetracycline class antibiotic, is one of the most effective antibiotics for treating A. baumannii infections in patients. Unfortunately, MIN resistance is spreading internationally and has begun to emerge in the United States. While efflux pumps are correlated with MIN resistant A. baumannii, clinical data suggests alternative mechanisms of MIN resistance. To explore the genetic basis for MIN resistance in A. baumannii we employed a machine learning model to predict genetic resistance correlates from clinical isolates. Mutations in ruvB, a DNA repair protein, were strongly correlated with MIN resistant clinical strains of A. baumannii .Consistent with the prediction, tn26 insertion in ruvB in A. baumannii strain AB5075, and deletion of ruvB in strain ATCC 19606, increased MIN minimum inhibitory concentrations to a level that exceeds the MIN resistance breakpoint. RuvB complexes with RuvA and RuvC to resolve Holliday junctions during recombination. However, only ruvB mutants showed the resistance phenotype; neither ruvA nor ruvC mutants were MIN resistant, suggesting loss of the activity of the complex was not the basis for resistance. We observed ruvB mutants produced increased biomass during planktonic growth relative to the other two ruv mutants. Upon examination, the ruvB::tn26 mutant had a 451% increase in biomass and 360% thicker biofilms relative to wildtype. We determined the disruption of ruvB lead to thicker biofilms and enriched in extracellular DNA (eDNA), and DNase I treatment collapsed the enhanced biofilm phenotype and markedly reduced tetracycline class MICs. FLAG-RuvA accumulated within the biofilm matrix in the absence of RuvB, supporting a model in which RuvA contributes to stabilization of eDNA-rich structures. In a murine pneumonia model, ruvB disruption did not significantly alter survival or pulmonary burden in untreated infection but reduced bacterial dissemination and increased minocycline resistance. Together, these findings reveal an unexpected connection between Holliday junction processing, eDNA-rich biofilm architecture, and antibiotic resistance in A. baumannii.

microbiology↗

bioRxiv2026

Azithromycin robustly synergizes with tetracyclines to overcome acquired minocycline resistance in Acinetobacter baumannii

Multidrug-resistant (MDR) Acinetobacter baumannii is a critical nosocomial pathogen with rapidly shrinking treatment options, and although minocycline (MIN) remains useful, resistance is increasingly common, highlighting the need for effective combination therapies. Here, we investigate azithromycin (AZM)-tetracycline synergism as a strategy to overcome acquired MIN resistance and define the antibiotic-specific drivers of this interaction. Using MIC90 and checkerboard fractional inhibitory concentration (FIC) assays, we tested AZM and MIN across multiple A. baumannii strains (AB5075, ATCC19606, BAA1710, BAA1789) in both bacteriological (CA-MHB) and physiologic (RPMI+) media and found AZM-MIN synergy to be robust across strains and media, with enhanced synergy in RPMI+. To determine whether this effect reflects a class-wide phenomenon, we systematically evaluated different macrolide-tetracycline combinations and observed that synergy occurred consistently in AZM containing pairs, identifying AZM (not tetracycline selection) as the dominant driver of synergy. Mechanistically, translation inhibition assays using an AB5075-luxCDABE reporter demonstrated that AZM uniquely sustained strong translational inhibition at multiple sub-inhibitory fractions, supporting a kinetic basis for synergy when combined with tetracyclines. Finally, AZM-MIN synergy was evaluated against 41 MDR isolates from the CDC-FDA Antimicrobial Resistance Isolate Bank, where synergism was detected in 8/41 strains and reduced the inhibitory MIN concentration below the CLSI resistance breakpoint for 4 isolates, indicating that AZM-based combinations can partially restore MIN susceptibility in resistant backgrounds. Together, these findings establish AZM as a potent and distinctive macrolide synergist with tetracyclines against MDR A. baumannii and support further exploration of AZM-tetracycline combination therapy to extend the clinical utility of MIN and mitigate selection for resistance.

microbiology↗

bioRxiv2022

Decoding Numeracy and Literacy in the Human Brain: Insights from MEG and MVPA

Numbers and letters are the fundamental building blocks of our everyday social interactions. Previous studies have focused on determining the cortical networks shaped by numeracy and literacy in the human brain, partially supporting the hypothesis of distinct neural circuits involved the processing of the two categories. In this study, we aim to investigate the temporal dynamics for number and letter processing. We present MEG data from two experiments (N=20 each). In the first experiment, single numbers, letter, and their respective false fonts (false numbers and false letters) were presented, whereas, in the second experiment, numbers, letters, and their respective false fonts were presented as a string of characters. We used multivariate pattern analysis techniques (time-resolved decoding and temporal generalization) testing the strong hypothesis that the neural mechanisms supporting letter and number processing can be logistically classified as categorically separate. Our results show a very early dissociation ([~]100 ms) between numbers, and letters when compared to false fonts. Number processing can be dissociated with similar accuracy when presented as isolated items or strings of characters, while letter processing shows dissociable classification accuracy for single items compared to strings. These findings reinforce the evidence indicating that early visual processing can be differently shaped by the experience with numbers and letters; this dissociation is stronger for strings compared to single items, thus showing that combinatorial mechanisms for numbers and letters could be categorically distinguished and influence early brain activity.

neuroscience↗