The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed. 

/pdf/antibiotics-in-the-clinical-pipeline-as-of-december-2022-16jjeayo.pdf

Antibiotics in the clinical pipeline as of December 2022

The human–bacterial association is long-known and well-established in terms of both augmentations of human health and attenuation. However, the growing incidents of nosocomial infections caused by the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp.) call for a much deeper understanding of these organisms. Adopting a holistic approach that includes the science of infection and the recent advancements in preventing and treating infections is imperative in designing novel intervention strategies against ESKAPE pathogens. In this regard, this review captures the ingenious strategies commissioned by these master players, which are teamed up against the defenses of the human team, that are equally, if not more, versatile and potent through an analogy. We have taken a basketball match as our analogy, dividing the human and bacterial species into two teams playing with the ball of health. Through this analogy, we make the concept of infectious biology more accessible.

/pdf/revisiting-eskape-pathogens-virulence-resistance-and-18u10618.pdf

Revisiting ESKAPE Pathogens: virulence, resistance, and combating strategies focusing on quorum sensing

A biofilm is an aggregation of surface-associated microbial cells that is confined in an extracellular polymeric substance (EPS) matrix. Infections caused by microbes that form biofilms are linked to a variety of animals, including insects and humans. Antibiotics and other antimicrobials can be used to remove or eradicate biofilms in order to treat infections. However, due to biofilm resistance to antibiotics and antimicrobials, clinical observations and experimental research clearly demonstrates that antibiotic and antimicrobial therapies alone are frequently insufficient to completely eradicate biofilm infections. Therefore, it becomes crucial and urgent for clinicians to properly treat biofilm infections with currently available antimicrobials and analyze the results. Numerous biofilm-fighting strategies have been developed as a result of advancements in nanoparticle synthesis with an emphasis on metal oxide np. This review focuses on several therapeutic strategies that are currently being used and also those that could be developed in the future. These strategies aim to address important structural and functional aspects of microbial biofilms as well as biofilms' mechanisms for drug resistance, including the EPS matrix, quorum sensing (QS), and dormant cell targeting. The NPs have demonstrated significant efficacy against bacterial biofilms in a variety of bacterial species. To overcome resistance, treatments such as nanotechnology, quorum sensing, and photodynamic therapy could be used. 

/pdf/therapeutic-strategies-against-biofilm-infections-3r9qhhtw.pdf

Therapeutic Strategies against Biofilm Infections

Interaction of RecA mediated SOS response with bacterial persistence, biofilm formation, and host response.

Harmless and resourceful treatment of waste activated sludge (WAS) have been the crucial goal for building environmental-friendly and sustainable society, while the synergistic realization approach is currently limited. This work skillfully utilized the disinfectant sodium dichloroisocyanurate (NaDCC) to simultaneously achieve the pathogenic potential inactivation (decreased by 60.1 %) and efficient volatile fatty acids (VFAs) recovery (increased by 221.9 %) during WAS anaerobic fermentation in rather cost-effective way (Chemicals costs:0.4 USD/kg VFAs versus products benefits: 2.68 USD/kg chemical). Mechanistic analysis revealed that the C=O and NCl bonds in NaDCC could spontaneously absorb sludge (binding energy -4.9 kJ/mol), and then caused the sludge disintegration and organic substrates release for microbial utilization due to the oxidizability of NaDCC. The disruption of sludge structure along with the increase of bioavailable fermentation substrates contributed to the selectively regulation of microbial community via enriching VFAs-forming microorganisms (e.g., Pseudomonas and Streptomyces) and reducing VFAs-consuming microorganisms, especially aceticlastic methanogens (e.g., Methanothrix and Methanospirillum). Correspondingly, the metabolic functions of membrane transport, substrate metabolism, pyruvate metabolism, and fatty acid biosynthesis locating in the central pathway of VFAs production were all upregulated while the methanogenic step was inhibited (especially acetate-type methanogenic pathway). Further exploration unveiled that for those enriched functional anaerobes were capable to activate the self-adaptive systems of DNA replication, SOS response, oxidative stress defense, efflux pump, and energy metabolism to counteract the unfavorable NaDCC stress and maintain high microbial activities for efficient VFAs yields. This study would provide a novel strategy for synergistic realization of harmless and resourceful treatment of WAS, and identify the interrelations between microbial metabolic regulations and adaptive responses. 

Disinfectant sodium dichloroisocyanurate synergistically strengthened sludge acidogenic process and pathogens inactivation: Targeted upregulation of functional microorganisms and metabolic traits via self-adaptation

Acinetobacter baumannii is the causative agent of various hospital‐acquired infections. Biofilm formation is one of the various antimicrobial resistance (AMR) strategies and is associated with high mortality and morbidity. Hence, it is essential to review the potential antibiofilm targets in A. baumannii and come up with different strategies to combat these potential targets. This review covers different pathways involved in the regulation of biofilm formation in A. baumannii like quorum sensing (QS), cyclic‐di‐GMP signaling, two‐component system (TCS), outer‐membrane protein (ompA), and biofilm‐associated protein (BAP). A newly discovered mechanism of electrical signaling‐mediated biofilm formation and contact‐dependent biofilm modulation has also been discussed. As biofilm formation and its maintenance in A. baumannii is facilitated by these potential targets, the detailed study of these targets and pathways can bring light to different therapeutic strategies such as anti‐biofilm peptides, natural and synthetic molecule inhibitors, QS molecule degrading enzymes, and other strategies. These strategies may help in suppressing the lethality of biofilm‐mediated infections. Targeting essential proteins/targets which are crucial for biofilm formation and regulation may render new therapeutic strategies that can aid in combating biofilm, thus reducing the recalcitrant infections and morbidity associated with the biofilm of A. baumannii.

Therapeutic strategies against potential antibiofilm targets of multidrug‐resistant Acinetobacter baumannii

Anti-persister strategies against stress induced bacterial persistence.

Several infections, such as pneumonia, urinary tract infections (UTIs), as well as bloodstream, skin, and soft tissue infections, are caused by Acinetobacter baumannii, a nosocomial pathogen and Gram-negative coccobacillus. Due to its resistance to a variety of medications, multidrug therapy, and occasionally pan therapies, this bacterium is a huge public health concern. Drug resistance is a big worry not only in A. baumannii, but it is also a major challenge in many other diseases. Antibiotic resistance, biofilm development, and genetic alterations are all linked to variables like the efflux pump. Efflux pumps are transport proteins involved in the extrusion of hazardous substrates from within cells into the external environment (including nearly all types of therapeutically relevant antibiotics). Both Gram-positive and Gram-negative bacteria, as well as eukaryotic organisms, contain these proteins. Efflux pumps may be specialized for a single substrate or can transport a variety of structurally dissimilar molecules (including antibiotics of many classes); these pumps have been linked to multiple drug resistance (MDR). There are five primary families of efflux transporters in the prokaryotic kingdom: MF (major facilitator), MATE (multidrug and toxic efflux), RND (resistance-nodulation-division), SMR (small multidrug resistance), and ABC (ATP-binding cassette). The efflux pumps and their types as well as the mechanisms of an efflux pump involved in multidrug resistance in bacteria have been discussed here. The main focus is on the variety of efflux pumps commonly found in A. baumannii, along with their mechanism by which they make this bacteria drug resistant. The efflux-pump-inhibitor-based strategies that are significant in targeting efflux pumps in A. baumannii have also been discussed. The connection of biofilm and bacteriophage with the efflux pump can prove as an efficient strategy for targeting efflux-pump-based resistance in A. baumannii. 

Different Efflux Pump Systems in Acinetobacter baumannii and Their Role in Multidrug Resistance.

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Interaction of RecA mediated SOS response with bacterial persistence, biofilm formation, and host response.

Therapeutic strategies against potential antibiofilm targets of multidrug‐resistant Acinetobacter baumannii

Anti-persister strategies against stress induced bacterial persistence.

Different Efflux Pump Systems in Acinetobacter baumannii and Their Role in Multidrug Resistance.