Maneesh Paul-Satyaseela

Antimicrobial resistance (AMR) is the ability of microbes to survive exposure to antimicrobials that were once effective against them. This is a major global crisis and public health challenge of the 21st century that is declared as a silent pandemic, with India among other countries considered one of the hotspots [R. Laxminarayan, A. Duse, C. Wattal, A. K. M. Zaidi, et al., Lancet Infect Dis 13:1057–1098, 2013, https://doi.org/10.1016/S1473-3099(13)70318-9 ]. The evolution of AMR in modern India’s context is embedded in a complex interplay of the timing of antibiotic introduction, a growing dense population, cultural inheritances, infectious disease burden, developing health systems, evolving drug market regulations, environmental and animal sector drivers, socioeconomic factors, and policy/implementation gaps. Central to this discussion are the human patient, animal, and environmental aspects of antibiotic overuse from the historical aspects of AMR in India broadly tracing from early antibiotic use to the current “One Health” challenge. It highlights cultural factors, the evolution of surveillance systems, policy responses, India’s efforts, and key lessons in antimicrobial stewardship.

The discovery of antimicrobials was an inflection point in human existence since it contributed enormously to the extension of the human lifespan. Among others, the invention of Enmetazobactam marks a significant milestone in the field of antimicrobial development, especially for India. It is a novel beta-lactamase inhibitor invented by scientists at Orchid Pharma in Chennai, India, and has garnered international attention for its potential to address antimicrobial resistance. It became the first new chemical entity invented in India, clinically developed by Allecra Therapeutics GmbH, to be approved by the U.S. Food & Drug Administration, with additional approvals from the European Medical Agency, the U.K.'s Medicine & Healthcare Products Regulatory Agency, and the Drug Controller General of India.

Antibiotic resistance, and, in a broader perspective, antimicrobial resistance (AMR), continues to evolve and spread beyond all boundaries. As a result, infectious diseases have become more challenging or even impossible to treat, leading to an increase in morbidity and mortality. Despite the failure of conventional, traditional antimicrobial therapy, in the past two decades, no novel class of antibiotics has been introduced. Consequently, several novel alternative strategies to combat these (multi-) drug-resistant infectious microorganisms have been identified. The purpose of this review is to gather and consider the strategies that are being applied or proposed as potential alternatives to traditional antibiotics. These strategies include combination therapy, techniques that target the enzymes or proteins responsible for antimicrobial resistance, resistant bacteria, drug delivery systems, physicochemical methods, and unconventional techniques, including the CRISPR-Cas system. These alternative strategies may have the potential to change the treatment of multi-drug-resistant pathogens in human clinical settings.

The COVID-19 pandemic presents a serious public health challenge in all countries. However, repercussions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on future global health are still being investigated, including the pandemic’s potential effect on the emergence and spread of global antimicrobial resistance (AMR). Critically ill COVID-19 patients may develop severe complications, which may predispose patients to infection with nosocomial bacterial and/or fungal pathogens, requiring the extensive use of antibiotics. However, antibiotics may also be inappropriately used in milder cases of COVID-19 infection. Further, concerns such as increased biocide use, antimicrobial stewardship/infection control, AMR awareness, the need for diagnostics (including rapid and point-of-care diagnostics) and the usefulness of vaccination could all be components shaping the influence of the COVID-19 pandemic. In this publication, the authors present a brief overview of the COVID-19 pandemic and associated issues that could influence the pandemic’s effect on global AMR.

A pandemic, by definition, involves the whole world being impacted by a common threat and calls for a united response. A highly virulent pathogen, the novel coronavirus (SARS-CoV-2) has affected every facet of modern life. The virus has revealed the world’s underlying inherent inequities, such as economic and food insecurity and availability of and access to a functional healthcare system, not to mention preparedness of nations to manage a coordinated pandemic response. For these reasons, Coronavirus disease (COVID-19) represents an unprecedented challenge to economies, healthcare systems, and nations alike. The closing of international and internal borders, physical distancing, and the resulting decrease in travel and trade have led countries to become insular geographically, socially, and economically. Somewhat ironically, this necessitates an increased need for greater collaboration between countries and other stakeholders to control the transmission of SARS-CoV-2 and better manage the global crisis upon us, so as to mitigate the long-term sequelae of this pandemic.

Candida albicansis a mucosal commensal organism in normal individuals, but is a major pathogen causing systemic and mucosal infections in immunocompromised individuals. Azoles have been very effective anti-fungal agents and the mainstay in treating opportunistic mold and yeast infections. Azole resistant strains have emerged compromising the utility of this class of drugs. It has been shown that azole resistance can be reversed by the co-administration of a histone deacetylase (HDAC) inhibitor, suggesting that resistance is mediated by epigenetic mechanisms possibly involving Hos2, a fungal deacetylase. We report here the cloning and functional characterization ofHOS2 (HighOsmolaritySensitive),a gene coding for fungal histone deacetylase fromC. albicans. Inhibition studies showed that Hos2 is susceptible to pan inhibitors such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), but is not inhibited by class I inhibitors such MS-275. Purified Hos2 protein consistently deacetylated tubulins, rather than histones from TSA-treated cells. Thisin vitroenzymatic assay, which is amenable to high throughput could be used for screening potent fungal Hos2 inhibitors that could be a potential anti-fungal adjuvant. Hos2 has been reported to be a putative NAD+ dependent histone deacetylase, a feature of sirtuins. We assayed for sirtuin activation with resveratrol and purified Hos2 protein and did not find any sirtuin activity.

Staphylococcus aureus (S. aureus) is important both as a nosocomial and community acquired pathogen causing various degrees of infections. Typing S. aureus has been a question that is still being addressed. Bacteriophage typing is still used as a golden standard for typing though molecular methods are investigated. In developing countries where neither molecular typing nor the bacteriophage typing methods can be routinely used, the recently developed capsular typing method can be considered as screening method. We compared capsular typing with bacteriophage typing of the strains isolated in Gulbarga, India. We observed that the typeability of capsular typing was significantly higher (96%) among the phage typed strains, and the predominant capsular type in the region was type-8. The data so generated can be used to group S. aureus based on capsules both as a screening prior to bacteriophage typing, and to identify capsular candidate for developing prophylactic and therapeutic alternatives.

Escherichia coli K1 is the most common Gram-negative bacillary organism causing neonatal meningitis. E. coli K1 binding to and invasion of human brain microvascular endothelial cells (HBMECs) is a prerequisite for its traversal of the blood-brain barrier (BBB) and penetration into the brain. In the present study, we identified NlpI as a novel bacterial determinant contributing to E. coli K1 interaction with HBMECs. The deletion of nlpI did not affect the expression of the known bacterial determinants involved in E. coli K1-HBMEC interaction, such as type 1 fimbriae, flagella, and OmpA, and the contribution of NlpI to HBMECs binding and invasion was independent of those bacterial determinants. Previous reports have shown that the nlpI mutant of E. coli K-12 exhibits growth defect at 42°C at low osmolarity, and its thermosensitive phenotype can be suppressed by a mutation on the spr gene. The nlpI mutant of strain RS218 exhibited similar thermosensitive phenotype, but additional spr mutation did not restore the ability of the nlpI mutant to interact with HBMECs. These findings suggest the decreased ability of the nlpI mutant to interact with HBMECs is not associated with the thermosensitive phenotype. NlpI was determined as an outer membrane-anchored protein in E. coli , and the nlpI mutant was defective in cytosolic phospholipase A ₂ α (cPLA ₂ α) phosphorylation compared to the parent strain. These findings illustrate the first demonstration of NlpI's contribution to E. coli K1 binding to and invasion of HBMECs, and its contribution is likely to involve cPLA ₂ α.