抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Antibiotic-resistant bacterial infections arising from acquired resistance and/or through biofilm formation necessitate the development of innovative 'outside of the box' therapeutics Nanomaterial-based therapies are promising tools to combat bacterial infections that are difficult to treat, featuring the capacity to evade existing mechanisms associated with acquired drug resistance In addition, the unique size and physical properties of nanomaterials give them the capability to target biofilms, overcoming recalcitrant infections In this Review, we highlight the general mechanisms by which nanomaterials can be used to target bacterial infections associated with acquired antibiotic resistance and biofilms We emphasize design elements and properties of nanomaterials that can be engineered to enhance potency Lastly, we present recent progress and remaining challenges for widespread clinical implementation of nanomaterials as antimicrobial therapeutics

Nanomaterial-based therapeutics for antibiotic-resistant bacterial infections

The cGAS-STING signalling pathway has emerged as a key mediator of inflammation in the settings of infection, cellular stress and tissue damage Underlying this broad involvement of the cGAS-STING pathway is its capacity to sense and regulate the cellular response towards microbial and host-derived DNAs, which serve as ubiquitous danger-associated molecules Insights into the structural and molecular biology of the cGAS-STING pathway have enabled the development of selective small-molecule inhibitors with the potential to target the cGAS-STING axis in a number of inflammatory diseases in humans Here, we outline the principal elements of the cGAS-STING signalling cascade and discuss the general mechanisms underlying the association of cGAS-STING activity with various autoinflammatory, autoimmune and degenerative diseases Finally, we outline the chemical nature of recently developed cGAS and STING antagonists and summarize their potential clinical applications

/pdf/the-cgas-sting-pathway-as-a-therapeutic-target-in-1ha5zhuhbm.pdf

The cGAS-STING pathway as a therapeutic target in inflammatory diseases.

Antibiotic Adjuvants: Rescuing Antibiotics from Resistance

Type III CRISPR-Cas systems in prokaryotes provide immunity against invading nucleic acids through the coordinated degradation of transcriptionally active DNA and its transcripts by the Csm effector complex. The Cas10 subunit of the complex contains an HD nuclease domain that is responsible for DNA degradation and two Palm domains with elusive functions. In addition, Csm6, a ribonuclease that is not part of the complex, is also required to provide full immunity. We show here that target RNA binding by the Csm effector complex of Streptococcus thermophilus triggers Cas10 to synthesize cyclic oligoadenylates (cAn; n = 2 to 6) by means of the Palm domains. Acting as signaling molecules, cyclic oligoadenylates bind Csm6 to activate its nonspecific RNA degradation. This cyclic oligoadenylate–based signaling pathway coordinates different components of CRISPR-Cas to prevent phage infection and propagation.

A cyclic oligonucleotide signaling pathway in type III CRISPR-Cas systems

Biofilms are communities of microorganisms that are attached to a surface and play a significant role in the persistence of bacterial infections. Bacteria within a biofilm are several orders of magnitude more resistant to antibiotics, compared with planktonic bacteria. Thus far, no drugs are in clinical use that specifically target bacterial biofilms. This is probably because until recently the molecular details of biofilm formation were poorly understood. Bacteria integrate information from the environment, such as quorum-sensing autoinducers and nutrients, into appropriate biofilm-related gene expression, and the identity of the key players, such as cyclic dinucleotide second messengers and regulatory RNAs are beginning to be uncovered. Herein, we highlight the current understanding of the processes that lead to biofilm formation in many bacteria.

https://www.future-science.com/doi/pdf/10.4155/fmc.15.6

Biofilm formation mechanisms and targets for developing antibiofilm agents

In the biofilm form, bacteria are more resistant to various antimicrobial treatments Bacteria in a biofilm can also survive harsh conditions and withstand the host's immune system Therefore, there is a need for new treatment options to treat biofilm-associated infections Currently, research is focused on the development of antibiofilm agents that are nontoxic, as it is believed that such molecules will not lead to future drug resistance In this review, we discuss recent discoveries of antibiofilm agents and different approaches to inhibit/disperse biofilms These new antibiofilm agents, which contain moieties such as imidazole, phenols, indole, triazole, sulfide, furanone, bromopyrrole, peptides, etc have the potential to disperse bacterial biofilms in vivo and could positively impact human medicine in the future

https://www.future-science.com/doi/pdf/10.4155/fmc.15.7

Agents that inhibit bacterial biofilm formation

https://pubs.rsc.org/en/content/articlepdf/2016/cc/c6cc03439j

Cyclic dinucleotide (c-di-GMP, c-di-AMP, and cGAMP) signalings have come of age to be inhibited by small molecules

Aim: Persistent activation of STING pathway is the basis for several autoimmune diseases. STING is activated by cGAMP, which is produced by cGAS in the presence of DNA. Results/methodology: HPLC-ba...

https://www.future-science.com/doi/pdf/10.4155/fmc-2017-0322

Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels.

Carbapenem-resistant (CR) Klebsiella pneumoniae has emerged as an urgent public health threat in many industrialized countries worldwide, including the United States. Infections caused by CR K. pneumoniae are difficult to treat because these organisms are typically resistant to multiple antibiotics, and the patients have significant comorbidities. Notably, there is high (∼50%) mortality among individuals with bacteremia caused by CR K. pneumoniae. Given the dearth of new antibiotics, and the recent convergence of multidrug resistance and hypervirulence, there is a critical need for alternative strategies for the treatment of CR K. pneumoniae infections. The capsule polysaccharide (CPS) of K. pneumoniae has long been viewed as an important virulence factor that promotes resistance to phagocytosis and serum bactericidal activity. Thus, the CPS has been targeted previously for the development of therapeutics and vaccines, although there is no licensed CPS-based vaccine or therapy for the treatment of CR K. pneumoniae infections. Here, we discuss immunoprophylactic and immunotherapeutic approaches that have been tested previously for the treatment of Klebsiella infections. We also suggest potential strategies to promote development of CPS-based vaccines and therapies for prevention and treatment of CR K. pneumoniae infections.

Clement Opoku-Temeng

Papers

Biofilm formation mechanisms and targets for developing antibiofilm agents

Agents that inhibit bacterial biofilm formation

Cyclic dinucleotide (c-di-GMP, c-di-AMP, and cGAMP) signalings have come of age to be inhibited by small molecules

Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels.

Klebsiella pneumoniae capsule polysaccharide as a target for therapeutics and vaccines.