Delineating the Plausible Molecular Vaccine Candidates and Drug Targets of Multidrug-Resistant Acinetobacter baumannii

Abstract

Nosocomial infections have become alarming with the increase of multidrug-resistant bacterial strains of Acinetobacter baumannii . Being the causative agent in ~80% of the cases, these pathogenic gram-negative species could be deadly for hospitalized patients, especially in intensive care units utilizing ventilators, urinary catheters, and nasogastric tubes. Primarily infecting an immuno-compromised system, they are resistant to most antibiotics and are the root cause of various types of opportunistic infections including but not limited to septicemia, endocarditis, meningitis, pneumonia, skin, and wound sepsis and even urinary tract infections. Conventional experimental methods including typing, computational methods encompassing comparative genomics, and combined methods of reverse vaccinology and proteomics had been proposed to differentiate and develop vaccines and/or drugs for several outbreak strains. However, identifying proteins suitable enough to be posed as drug targets and/or molecular vaccines against the multidrug-resistant pathogenic bacterial strains has probably remained an open issue to address. In these cases of novel protein identification, the targets either are uncharacterized or have been unable to confer the most coveted protection either in the form of molecular vaccine candidates or as drug targets. Here, we report a strategic approach with the 3,766 proteins from the whole genome of A. baumannii ATCC19606 (AB) to rationally identify plausible candidates and propose them as future molecular vaccine candidates and/or drug targets. Essentially, we started with mapping the vaccine candidates (VaC) and virulence factors (ViF) of A. baumannii strain AYE onto strain ATCC19606 to identify them in the latter. We move on to build small networks of VaC and ViF to conceptualize their position in the network space of the whole genomic protein interactome (GPIN) and rationalize their candidature for drugs and/or molecular vaccines. To this end, we propose new sets of known proteins unearthed from interactome built using key factors, KeF, potent enough to compete with VaC and ViF. Our method is the first of its kind to propose, albeit theoretically, a rational approach to identify crucial proteins and pose them for candidates of vaccines and/or drugs effective enough to combat the deadly pathogenic threats of A. baumannii .

Proteomic Analyses of Acinetobacter baumannii Clinical Isolates to Identify Drug Resistant Mechanism

“…Through the study of the mechanism of multidrug resistance of A.baumannii , treatment can be adopted for its resistance mechanism to improve the success rate of treatment of A.baumannii infection, such as using engineered endolysin to degrade bacterial peptidoglycan to replace carbapenem drugs ( Lee et al., 2017 ) or add certain compounds that can increase the energy production of bacteria and enhance the permeability of their cell membranes during antibiotic treatment to promote the therapeutic effect of antibiotics ( Shin and Park, 2015 ). The development of vaccines against drug-resistant-related proteins is also another effective strategy to solve drug-resistant bacterial infections ( Mujawar et al., 2019 ). This study uses plenty of isolates for comparative and comprehensive analysis, however, because these isolates were isolated from the same hospital and might have similar genetic phenotypes, we still need further study like expanding sample sources or sequencing these isolates to found the genetic mechanism.…”

“…Nosocomial infections caused by multidrug-resistant (MDR) bacteria strains are a serious problem worldwide in decades. Acinetobacter baumannii has become one of the most common species that cause nosocomial infections and healthcare-associated infections such as bacteremia, pneumonia, meningitis, skin and wound infections, and urinary tract infection due to its strong biofilm formation ability and the ability to resist nutrient deprivation and antibiotics ( Dijkshoorn et al., 2007 ; Shin and Park, 2015 ; Mujawar et al., 2019 ). The traditional first-line treatment of A. baumannii uses carbapenem antibiotics such as imipenem, but since the early 1990s, there have been reports of outbreaks caused by imipenem-resistant A. baumannii ( Tankovic et al., 1994 ).…”

Strategic Role Players of Important Antimicrobial-Resistant Pathogens

“…Several health interventions have been proposed as alternatives to current antibiotic therapy and prevent the resistant mechanisms of which, the development of new drug classes, use of vaccines or other therapeutic strategies are noteworthy (Figure 4) [59]. In fact, using computational approaches, certain proteins and/or phenotypes, having plausible involvement in antibiotic resistance, are proposed [60][61][62][63][64] as discussed below.…”

Designing Multi-Antigen Vaccines Against Acinetobacter baumannii Using Systemic Approaches

“…The use of computational methods together with the availability of multiple sequenced genomes for bacterial pathogens has facilitated the rational identification of antigens over reductionist and empirical approaches for vaccine/mAb design, a protocol known as reverse vaccinology (RV) (18). Multiple studies employing different RV methodologies for A. baumannii antigen identification have been published since 2013 (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). In general, most RV pipelines are based on a reduced number of calculable features subjected to decision schemas or machine learning algorithms (29).…”