Biology subjects

Rao, R. S. P.

Publications and source records attributed to Rao, R. S. P..

8 recordsLinked to original sources

bioRxiv2024

Azole resistance: Patterns of amino acid substitutions in Candida sterol 14α-demethylase

The emergence of azole-resistant Candida infections is a major concern. A key mechanism is the gain of resistance through amino acid substitutions in the sterol 14-demethylase, the main target of azole drugs. While numerous resistant substitutions are known, the pattern of such substitutions is unclear. We hypothesized that the resistant substitutions occur disproportionately at the azole-binding sites. We compiled 2,222 instances of azole-resistant substitutions from the literature and performed extensive computational sequence analyses. Altogether there were 169 known substitutions at 133 sites in sterol 14-demethylases of seven Candida species, whereas C. albicans alone had 120 substitutions at 97 sites. Just 10 sites and 18 substitutions (such as Y132F/H, K143R, D116E, and G464S) accounted for 75% of the total instances. Only about 48% of the sites were present within the previously recognized hotspot regions, while just 33% of the known azole-interacting residues had known resistant substitutions, most of them with only a few instances. The literature data on azole-resistant substitutions in Candida appear to be highly biased as a few substitutions such as Y132F/H and K143R were preferentially sought and reported with over 1000 instances, while there were also numerous reports of "resistant" substitutions in azole-susceptible Candida isolates. Our study provides interesting perspectives into azole resistance.

bioinformatics↗

bioRxiv2023

Azole resistance: Insights from Y132 substitutions in Candida sterol 14α-demethylase

BackgroundAzole-resistant Candida infections are on the rise. Resistant substitutions at Y132 in sterol 14-demethylase, the key target of azole drugs, are frequent. However, it is unclear why only some Y132 substitutions are favoured or how they exert differential effects on different azoles. Materials and MethodsReported instances of Y132 substitutions were collected from the literature. Extensive molecular dynamics simulations of sterol 14-demethylase bound to fluconazole or VT1161 (VT1) were performed, and the ligand-binding free energies were computed to quantify the effects of various Y132 substitutions on azole binding/interactions. ResultsThree azole-resistant substitutions, Y to C/F/H, were reported at residue position 132 in sterol 14-demethylase. The Y132H was the most common substitution in C. albicans, while it was Y132F in other species. Ligand-binding free energies were -13.81 kcal/mol and -35.04 kcal/mol for fluconazole and VT1, respectively. There were differences in the ligand-binding free energies after substitutions compared to the wild type protein. ConclusionY132F and Y132H were the most frequent substitutions in Candida sterol 14-demethylase. Far higher binding free energy of fluconazole in comparison with VT1 might partly explain its susceptibility to azole-resistant substitutions. The results give key insights into azole resistance, and antifungal drug discovery and optimization.

bioinformatics↗

bioRxiv2023

Gut feeling: Extent of virulence and antibiotic resistance genes in Helicobacter pylori and campylobacteria

BackgroundHelicobacter pylori, a member of campylobacteria, is the leading cause of chronic gastritis and gastric cancer. Virulence and antibiotic resistance of H. pylori are of great concern to public health. However, the relationship between virulence and antibiotic resistance genes in H. pylori in relation to other campylobacteria remains unclear. Materials and MethodsBy using the virulence and comprehensive antibiotic resistance databases, we explored all available 354 complete genomes of H. pylori and compared it with 90 species of campylobacteria for virulence and antibiotic resistance genes/proteins. ResultsOn average, H. pylori had 129 virulence genes, highest among Helicobacter spp. and 71 antibiotic resistance genes, one of the lowest among campylobacteria. Just 2.6% of virulence genes were shared by all campylobacterial members, whereas 9.4% were unique to H. pylori. The cytotoxin-associated genes (cags) seemed to be exclusive to H. pylori. Majority of the isolates from Asia and South America were cag2-negative and many antibiotic resistance genes showed isolate-specific patterns of occurrence. Just 15 (8.8%) antibiotic resistance genes, but 103 (66%) virulence genes including 25 cags were proteomically identified in H. pylori. Arcobacterial members showed large variation in the number of antibiotic resistance genes and there was a positive relation with the genome size. ConclusionLarge repository of antibiotic resistance genes in campylobacteria and a unique set of virulence genes might have important implications in shaping the course of virulence and antibiotic resistance in H. pylori.

bioinformatics↗

bioRxiv2023

Functional network analysis identifies multiple virulence and antibiotic resistance systems in Stenotrophomonas maltophilia

Stenotrophomonas maltophilia, an emerging multidrug-resistant opportunistic bacterium in humans is of major concern for immunocompromised individuals for causing pneumonia and bloodborne infections. This bacterial pathogen is associated with a considerable fatality/case ratio, with up to 100%, when presented as hemorrhagic fever. It is resistant to commonly used drugs as well as to antibiotic combinations. In-silico based functional network analysis is a key approach to get novel insights into virulence and resistance in pathogenic organisms. This study included the protein-protein interaction (PPI) network analysis of 150 specific genes identified for antibiotic resistance mechanism and virulence pathways. Eight proteins, namely, pilL, fliA, Smlt2260, Smlt2267, cheW, Smlt2318, cheZ, and fliM were identified as hub proteins. Further docking studies of selected phytochemicals were performed against the identified hub proteins. Deoxytubulosine and Corosolic acid were found to be potent inhibitors of hub proteins of pathogenic S. maltophilia based on protein-ligand interactive study. Further pharmacophore studies are warranted with these molecules to develop them as novel antibiotics against S. maltophilia.

bioinformatics↗

bioRxiv2022

Prevalence and heterogeneity of antibiotic-resistant genes in Orientia tsutsugamushi and other rickettsial genomes

Despite a million infections every year and an estimated one billion people at risk, scrub typhus is regarded as a neglected tropical disease. The causative bacterium Orientia tsutsugamushi, a member of rickettsiae, seems to be intrinsically resistant to several classes of antibiotics. The emergence of antibiotic-resistant scrub typhus is likely to become a global public health concern. Yet, it is unknown as to how common antibiotic-resistant genes are in O. tsutsugamushi, and how variable these loci are among the genomes of rickettsiae. By using the comprehensive antibiotic resistance database, we explored 79 complete genomes from 24 species of rickettsiae for putative antibiotic-resistant loci. There were 244 unique antibiotic-resistant genes in rickettsiae. Both the total and unique antibiotic-resistant genes in O. tsutsugamushi were significantly less compared to other members of rickettsiae. However, antibiotic-resistant genes in O. tsutsugamushi genomes were more unique and highly variable. Many genes such as resistant versions of evgS, and vanS A/G were present in numerous copies. These results will have important implications in the context of antibiotic-resistant scrub typhus.

bioinformatics↗

bioRxiv2022

Seasonal dynamics and polyphenism of butterfly communities in the coastal plains of central Western Ghats, India

Long-term socioeconomic progress requires a healthy environment/ecosystem, but anthropogenic activities cause environmental degradation and biodiversity loss. Constant ecological monitoring is therefore necessary to assess the state of biodiversity and ecological health. However, baseline data is lacking even for ecologically sensitive regions such as the Western Ghats. We looked at the seasonality and polyphenism of butterflies of the central Western Ghats to get baseline population patterns on these charismatic taxa. We recorded 43118 individuals (175 species) using fortnightly time-constrained counts for two consecutive years, and found the peak abundance (49% of the total individuals) in post-monsoon period (Oct to Jan). The seasonal abundance was correlated with the overall increase in species richness. Habitat differences were stronger than seasonality as samples clustered based on sites. Several species also displayed polyphenism with distinct distributions of wet and dry season forms. Seasonal equitability and indicator species analysis showed distinct inter-species differences in seasonality patterns. This work provides key baseline data on the seasonal dynamics of butterflies of the Western Ghats in the context of climate change and conservation, and will help in future monitoring of this ecologically sensitive region using butterflies.

ecology↗

bioRxiv2021

Ecological interactions: Patterns of host utilization by tropical butterflies

Structural complexity of ecological networks facilitate the functional robustness of natural ecosystems. Threatened by the human actions such as habitat destruction and climate change, species may be more or less prone to ecological perturbations depending on the nature of their interactions. We examined the host network of tropical butterflies from the Indian region to see their level of interconnectedness. We manually curated larval host utilization data for 1053 butterflies of India. About 98.8% of species that occur pan-India and 90.6% of species exclusive to the Western Ghats had known hosts whereas it was only 25.9% for species exclusive to north-east India. There were 2589 unique butterfly-host interactions comprising 519 butterfly species and their 1091 known hosts. However, nearly 30% of the species had only single hosts. The Fabaceae and Poaceae were the key host families that accounted for 32.8% of the interactions. There were clear host preferences and monocots hosted disproportionately more butterfly species and interactions. Vanessa cardui had at least 39 known hosts while Ochlandra travancorica supported 19 butterfly species. There were 2693 species-pairs and 4226 interactions among 469 butterflies due to shared hosts. Many butterfly species that have relatively few/unique hosts might be vulnerable in the context of habitat destruction and climate change. This work has great relevance to the ecology and conservation of butterflies in India.

ecology↗

bioRxiv2021

Evolutionary dynamics of indels in SARS-CoV-2 spike glycoprotein

SARS-CoV-2, responsible for the current COVID-19 pandemic that claimed over 4.2 million lives, belongs to a class of enveloped viruses that undergo quick evolutionary adjustments under selection pressure. Numerous variants have emerged in SARS-CoV-2 that are currently posing a serious challenge to the global vaccination effort and COVID-19 management. The evolutionary dynamics of this virus are only beginning to be explored. In this work, we have analysed 1.79 million spike glycoprotein sequences of SARS-CoV-2 and found that the virus is fine-tuning the spike with numerous amino acid insertions and deletions (indels). Indels seem to have a selective advantage as the proportions of sequences with indels were steadily increasing over time, currently at over 89%, with similar trends across countries/variants. There were as many as 420 unique indel positions and 447 unique combinations of indels. Despite their high frequency, indels resulted in only minimal alteration, including both gain and loss, of N-glycosylation sites. As indels and point mutations are positively correlated and sequences with indels have significantly more point mutations, they have implications in the context of evolutionary dynamics of the SARS-CoV-2 spike glycoprotein.

bioinformatics↗