Biology subjects

Sau, S.

Publications and source records attributed to Sau, S..

11 recordsLinked to original sources

bioRxiv2026

Exploiting NDH-2 Vulnerability: Quinolines as Antitubercular Agents

Mycobacterium tuberculosis possesses a flexible metabolic system helping it to survive inside the host. The type II NADH dehydrogenase, composed of Ndh and NdhA, essential for bacilli, is a promising drug target. Based on ATP depletion values, two quinoline scaffolds were shortlisted after screening of a library of drug like molecules. Structurally, both 64-9C and 64-9D carry ester moieties at the 5- and 8-positions of the quinoline core, respectively. Ease to re-synthesise 64-9D resulted in synthesis of a focused library of compounds, with MIC values of 0.25-4 g/mL, consistent with ATP depletion. These compounds exhibited bactericidal activity against non-replicating mycobacteria, and showed potent efficacy against multidrug-resistant isolates. Altered, intracellular NADH/NAD+ ratio and reduced respiration was indicative of oxidative phosphorylation inhibition. Inhibition of the purified recombinant NDH protein uncompetitively, SNPs in gene encoding NDH-2 for selected one step mutants and, molecular modelling of 4FQN and 2FQN validated NDH-2 as a target for these compounds. The derivative 2FQN exhibited dose-dependent bactericidal efficacy in mice, underscoring the potential of the series as a promising anti-tuberculosis candidates.

microbiology↗

bioRxiv2025

Repurposing ethacridine as a potent MMPL3 Inhibitor for the treatment of tuberculosis

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis, remains a major global health threat, particularly with the rise of multidrug-resistant and extensively drug-resistant strains. This has renewed interest in repurposing existing drugs and exploring new cellular targets. The mycobacterial cell envelope is a key barrier to antibiotics and an attractive site for therapeutic intervention. In this study, we identify the FDA-approved drug ethacridine as a strong inhibitor of MmpL3, an essential transporter required for exporting trehalose monomycolate and building the cell wall. Computational docking and molecular dynamics indicate that ethacridine engages the MmpL3 binding pocket at residues also targeted by SQ109. Ethacridine shows potent activity against drug-sensitive and resistant Mtb isolates, with an MIC of 1 g/mL, and remains effective against non-replicating bacteria and intracellular infection. Ethacridine-resistant mutants, overexpression strains, and a spheroplast TMM-flipping assay confirm MmpL3 as the target. The compound also disrupts the membrane potential, and flow-cytometry assays

microbiology↗

bioRxiv2025

Targeting Metabolic Vulnerabilities: Valinomycin Augments the Potency of Bioenergetic Inhibitors in Combatting Drug-Resistant and Dormant Mycobacterium tuberculosis

Tuberculosis (TB) treatment is hampered by monotherapy limitations and phenotypic drug tolerance, citing the need for effective drug combinations. The mycobacterial electron transport chain (ETC), crucial for oxidative phosphorylation and ATP production in dormant Mycobacterium tuberculosis (Mtb), is a key target. This study investigates combining established bioenergetic inhibitors-bedaquiline (BDQ), telacebec (Q203), and clofazimine (CFZ) with the potassium ionophore valinomycin, which disrupts the proton motive force (pmf). We demonstrated that valinomycin significantly potentiated the anti-TB activity of these inhibitors against both replicating and nutrient-starved non-replicating Mtb. Checkerboard assays revealed synergistic activity with BDQ and additive effects with Q203 and CFZ, correlated with a two to three-fold reduction in ATP IC50 values. Critically, valinomycin converted the bacteriostatic activity of the inhibitors at sub-MIC concentration into bactericidal killing in time-dependent killing assay, achieving sterilization. This lethal synergy for the combinations was also observed in a THP-1 macrophage intracellular model for TB. Respiration assays confirmed that the combinations collectively halted oxygen consumption. We conclude that concurrently targeting specific ETC on Mtbs bioenergetics. This strategy, particularly the BDQ/valinomycin synergy, represents a promising cornerstone for developing novel sterilizing regimens to shorten TB therapy and overcoming drug tolerance.

microbiology↗

bioRxiv2025

The Elg1 Replication Factor C-like complex safeguards cells from replication stress through a noncanonical pathway independent of the Mec1-Rad53 axis

The Elg1 Replication Factor C-like complex (Elg1-RLC) that functions as a PCNA unloader, is known to be involved in multiple DNA replication/repair-related activities from yeast to humans. By exploiting disassembly-prone PCNA mutants, we reveal that Elg1-RLC uses its PCNA unloading activity to counter the DNA-alkylating agent methyl-methanesulfonate (MMS)-mediated slow progression of replication forks. Despite having a largely functional DNA Damage Response (DDR), the viability loss of elg1{Delta}-DDR double mutants, in the presence of MMS, matches that of mec1{Delta} and rad53{Delta} cells, deficient for the central checkpoint kinases. This suggests that elg1{Delta}-DDR double mutants experience replication fork collapse when exposed to MMS. Indeed, in response to MMS, accumulation of Rad52 foci in the replicative elg1{Delta}-DDR cells supports this possibility. However, the failure of rescuing elg1{Delta}-DDR mutants by elevating dNTP levels (by deleting the ribonucleotide reductase SML1) eliminates the possibility of a Rad53-regulated dNTP shortage-mediated fork collapse. Thus, we propose a S-phase checkpoint regulatory role of Elg1-RLC that works through a noncanonical pathway parallel to the canonical one. Collectively, our findings suggest a model in which Elg1-RLC, by timely unloading chromatin-bound PCNA from the damaged/stalled forks, coordinates the DDR pathways to safeguard the integrity of replication forks under replication stress.

molecular biology↗

bioRxiv2023

Does novelty influence foraging decision of a scavenger?

Acquiring knowledge about the environment is crucial for survival. Animals, often driven by their explorative tendencies, gather valuable information regarding food resources, shelter, mating partners, etc. While neophilia, or the preference for novel environmental stimuli or objects, can promote exploratory behaviour, neophobia, or avoidance of novel environmental stimuli, can constrain such behaviour. Neophobia can reduce predation risk, yet decreased exploratory behaviour resulting from it may limit the ability to discover potentially highly rewarding resources. Dogs (Canis familiaris) living in semi-urban and urban environments as free-ranging populations are, although subject to various selection forces, typically have negligible predation pressure. These dogs are scavengers in human-dominated environments; thus, selection against object-neophobia can provide benefits when searching for novel food resources. Although pet and captive pack-living dogs are known to exhibit neophilia when provided with novel objects, little is known about free-ranging dogs behavioural responses to novel objects, particularly in foraging contexts. Using an object choice experiment, we tested 274 free-ranging dogs from two age classes, adult and juvenile, to investigate their object-neophobia in a scavenging context. We employed a betweensubject study design, providing dogs with a familiar and a potentially novel object, both baited with equal but (partially)hidden food rewards. Adult and juvenile dogs significantly inspected the novel object first compared to the familiar one, even when we reduced the visual obscurity of the familiar object, i.e., when the hidden food reward was partially visible. Furthermore, novel objects with varying strengths of olfactory cues (baited vs. false-baited) were inspected comparably by adults and juveniles. No significant differences were found in the latencies to inspect the objects. These results indicate that free-ranging dogs, evidently from an early ontogenic phase, do not show object-neophobia, as demonstrated by their preference for novel over familiar food sources. We conclude that little to no constraint of neophobia on exploratory behaviour, yet selection for object-neophilia in semi-urban and urban-dwelling animals can guide foraging decision-making processes, providing adaptive benefits.

animal behavior and cognition↗

bioRxiv2023

Toxic metal uptake by oyster mushrooms grown in sugarcane bagasse

Fungiculture or Mushroom Cultivation is rapidly expanding throughout the world. It is further catalyzed by its high nutritional value and increased market demand. Additionally, the method of cultivation does not require much space and the per unit production is very high compared to other crops. Bagasse is the byproduct left after extracting the juice from sugarcane. It has been speculated that bagasse can be an excellent substrate due to its high carbohydrate and mineral content (Hoa et al., 2015). In the experiment spawns of Oyster Mushroom were inoculated in bagasse collected from industries. Remarkable growth of mushrooms in short period of time was observed. However, the metal toxicity being our primary concern in this experiment, AAS (Atomic Absorption Spectrometry) Test was used to detect the heavy metal ion concentrations in both the bagasse and the fruiting bodies of mushrooms. The concentrations of metals calculated are as follows, in bagasse (mg/kg): Cadmium - 0.015, Arsenic - 8.56, Copper-12.47, Chromium-9.17, Mercury - less than 0.01, and in mushroom (mg/kg): Cd - 0.022, As - 10.12, Cu - 14.29, Cr - 7.59, Hg - less than 0.01. These results indicated biomagnification of metal ion concentration in the mushrooms up taken from bagasse. These metals, in such high concentrations are lethal and causes many diseases in humans and other animals. Hence, from this experiment it can be deduced, that though bagasse is an excellent substrate for mushroom cultivation, the toxicity of metal ions present in it in such high concentrations overshadow the earlier benefits of bagasse as a good substrate. However, it has been proposed that if such metals are removed or their concentrations are lowered then the earlier mentioned benefits of bagasse are restored.

ecology↗

bioRxiv2020

Access to PCNA by Srs2 and Elg1 controls the choice between alternative repair pathways in yeast

During DNA replication stalling can occur when the replicative DNA polymerases encounter lesions or hard-to replicate regions. Under these circumstances the processivity factor PCNA gets ubiquitylated at lysine 164, inducing the DNA damage tolerance (DDT) mechanisms that can bypass lesions encountered during DNA replication. PCNA can also be SUMOylated at the same residue or at lysine 127. Surprisingly, pol30-K164R mutants display a higher degree of sensitivity to DNA damaging agents than pol30-KK127,164RR strains, unable to modify any of the lysines. Here we show that in addition to trans-lesion synthesis and strand-transfer DTT mechanisms, an alternative repair mechanism ("salvage recombination") that copies information from the sister chromatid, is repressed by the recruitment of Srs2 to SUMOylated PCNA. Overexpression of Elg1, the PCNA unloader, or of the recombination protein Rad52 allows its activation. We dissect the genetic requirements for this pathway, as well as the interactions between Srs2 and Elg1.

genetics↗

bioRxiv2019

\"Bolder\" together - response to human social cues in free-ranging dogs

Interspecific interactions within an ecosystem have different direct and indirect effects on the two interacting species. In the urban environment, humans are a part of an interaction network of several species. While indirect human influence on different urban species has been measured extensively, experimental studies concerning direct human influence are lacking. In this study, we tested interactions between groups of urban free-ranging dogs (Canis lupus familiaris) and solitary unfamiliar humans in ecologically relevant contexts. We provided different sets of dogs with four commonly used human social cues (neutral, friendly, low and high impact threatening) to understand their responses at the group-level and identify potential inter-individual differences. Finally, we compared data from a previous study to investigate the differences in behavioural outcomes between solitary and groups of dogs while interacting with humans. The study not only strengthens the idea of situation-relevant responsiveness in free-ranging dogs but also highlights the minute differences between solitary and group-level reactions in the form of higher approach and less anxious behaviour of groups towards the unfamiliar human. Additionally, we report inter-individual differences and the effect of sex while responding to the threatening cues. Our study suggests a direct benefit of group-living over a solitary lifestyle in free-ranging dogs while interacting with humans in the streets.\n\nSummary statementFree-ranging dogs can benefit by living in groups over a solitary lifestyle while interacting with unfamiliar humans in urban habitats irrespective of having significant inter-individual differences.

animal behavior and cognition↗

bioRxiv2019

Cooperation only for high rewards - a solvable task-based study on free-ranging dogs

The benefits of group living mostly surpass the disadvantages like sharing of resources and competition over food, space and mates, driving the evolution of social organization. Group living can be facilitated by social tolerance and cooperation among the group members. Social canids (e.g. wolves) display cooperative breeding, hunting, and prosocial activities in different contexts. Unlike cooperative pack-living wolves (Canis lupus lupus), their descendants, domesticated dogs (Canis lupus familiaris), show varying levels of associations from solitary to stable social groups. Free-ranging dogs are group-living but prefer to forage solitarily, hence providing an excellent opportunity for investigating social tolerance and coordinated task performance among the members in various situations. We tested 113 adult-only groups of free-ranging dogs in three different tasks to investigate group responses and performance in problem-solving situations in the presence of an unfamiliar human. Task 1 (unfamiliar, single food reward) and 2 (familiar, single food reward) examined group responses and cooperation from the perspective of familiarity, while Task 3 (familiar, multiple food rewards) enabled us to test whether increased food rewards promote social tolerance and food sharing among the group members. Regardless of significantly higher performance in Task 2 compared to Task 1, cooperation and food sharing were significantly lower in both. Task 3 revealed a strong positive correlation between food sharing and social tolerance, but not between success and social tolerance, suggesting a tendency for cooperation. We conclude that context-dependent cooperation and tolerance among group members facilitate group-living in free-ranging dogs.\n\nSignificance statementGroup living is a common phenomenon in the animal world where the members of a group show social tolerance and co-operative behaviours towards each other. This need for cooperative intents increases manifolds while groups face different problem-solving situations in their day to day lives. Here, we tested a large number of free-ranging dog groups to understand general cooperative intents such as social tolerance and food sharing in different problem-solving conditions. We found shreds of evidence of context-dependent cooperation and social tolerance among group members with minimal display of aggression. It is not adaptive for the dogs to fight or display aggression over resources. Alternatively, use of subtle cues such as display of dominance and subordination seem to be more plausible mechanisms for the development of efficient scavenging strategies and maintaining hierarchy.

animal behavior and cognition↗

bioRxiv2019

A staphylococcal cyclophilin carries a single domain and unfolds via the formation of an intermediate that preserves cyclosporin A binding activity

Cyclophilin (Cyp), a peptidyl-prolyl cis-trans isomerase (PPIase), acts as a virulence factor in many bacteria including Staphylococcus aureus. The enzymatic activity of Cyp is inhibited by cyclosporin A (CsA), an immunosuppressive drug. To precisely determine the unfolding mechanism and the domain structure of Cyp, we have investigated a chimeric S. aureus Cyp (rCyp) using various probes. Our limited proteolysis and the consequent analysis of the proteolytic fragments indicate that rCyp is composed of one domain with a short flexible tail at the C-terminal end. We also show that the urea-induced unfolding of both rCyp and rCyp-CsA is completely reversible and proceeds via the synthesis of at least one stable intermediate. The secondary structure, tertiary structure, and the hydrophobic surface area of no intermediate are fully identical to those of other intermediate or the related native protein. Further analyses reveal no loss of CsA binding activity in rCyp intermediate. The thermodynamic stability of rCyp was also significantly increased in the presence of CsA, recommending that this protein could be employed to screen new CsA derivatives in future.

biochemistry↗

bioRxiv2018

Free-ranging dogs understand human intentions and adjust their behavioral responses accordingly

Domestic dogs (Canis lupus familiaris) are remarkably sensitive and responsive while interacting with humans. Pet dogs are known to have social skills and abilities to display situation-specific responses, but there is lack of information regarding free-ranging dogs which constitute majority of the worlds dog population. Free-ranging dogs found in most of the developing countries interact constantly with familiar and unfamiliar humans receiving both positive and negative behavior. Thus, understanding human intentions and subsequent behavioral adjustments are crucial for dogs that share habitats with humans. Here we subjected free-ranging dogs to different human social communicative cues (friendly and threatening - low and high), followed by a food provisioning phase and tested their responsiveness. Dogs exhibited higher proximity seeking behavior as a reaction to friendly gesture whereas, they were prompted to maintain distance depending on the impact of the threatening cues. Interestingly, only the high-impact threatening showed to have a persistent effect which also remained during the subsequent food provisioning phase. An elevated approach in the food provisioning phase elicited the dependency of free-ranging dogs on humans for sustenance. Our findings suggest that free-ranging dogs demonstrate behavioral plasticity on interacting with humans; which provides significant insights into the establishment of the dog-human relationship on streets.

animal behavior and cognition↗